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  • 101. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    De Bont, Evelina S.
    de Haas, Valerie
    De Moerloose, Barbara
    Forestier, Erik
    Ha, Shau Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Reedijk, Ardine
    Saks, Kadri
    Zeller, Bernward
    Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 102. Heath, Simon C.
    et al.
    Gut, Ivo G.
    Brennan, Paul
    McKay, James D.
    Bencko, Vladimir
    Fabianova, Eleonora
    Foretova, Lenka
    Georges, Michael
    Janout, Vladimir
    Kabesch, Michael
    Krokan, Hans E.
    Elvestad, Maiken B.
    Lissowska, Jolanta
    Mates, Dana
    Rudnai, Peter
    Skorpen, Frank
    Schreiber, Stefan
    Soria, José M.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Meneton, Pierre
    Herçberg, Serge
    Galan, Pilar
    Szeszenia-Dabrowska, Neonilia
    Zaridze, David
    Génin, Emmanuel
    Cardon, Lon R.
    Lathrop, Mark
    Investigation of the fine structure of European populations with applications to disease association studies2008In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, no 12, p. 1413-1429Article in journal (Refereed)
    Abstract [en]

    An investigation into fine-scale European population structure was carried out using high-density genetic variation on nearly 6000 individuals originating from across Europe. The individuals were collected as control samples and were genotyped with more than 300 000 SNPs in genome-wide association studies using the Illumina Infinium platform. A major East-West gradient from Russian (Moscow) samples to Spanish samples was identified as the first principal component (PC) of the genetic diversity. The second PC identified a North-South gradient from Norway and Sweden to Romania and Spain. Variation of frequencies at markers in three separate genomic regions, surrounding LCT, HLA and HERC2, were strongly associated with this gradient. The next 18 PCs also accounted for a significant proportion of genetic diversity observed in the sample. We present a method to predict the ethnic origin of samples by comparing the sample genotypes with those from a reference set of samples of known origin. These predictions can be performed using just summary information on the known samples, and individual genotype data are not required. We discuss issues raised by these data and analyses for association studies including the matching of case-only cohorts to appropriate pre-collected control samples for genome-wide association studies.

  • 103.
    Hedman, Åsa K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Mendelson, Michael M.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Boston, MA 02215 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew Senior Life, Boston, MA USA..
    Irvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Demissie, Serkalem
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Cupples, L. Adrienne
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Krauss, Ronald M.
    Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY 40506 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA..
    Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 1, article id UNSP e001487Article in journal (Refereed)
    Abstract [en]

    Background- Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results- To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P < 1.08E-07) and replicated 33 (at Bonferroni-corrected P < 0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglyceridesand high-density lipoprotein cholesterol (HDL- C; cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P= 7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P= 0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (P-TC = 0.004, PHDL-C = 0.008 and P-triglycerides = 0.00003) and coronary heart disease ( P= 0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. Conclusions-We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.

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  • 104. Heid, Iris M
    et al.
    Jackson, Anne U
    Randall, Joshua C
    Winkler, Thomas W
    Qi, Lu
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Zillikens, M Carola
    Speliotes, Elizabeth K
    Mägi, Reedik
    Workalemahu, Tsegaselassie
    White, Charles C
    Bouatia-Naji, Nabila
    Harris, Tamara B
    Berndt, Sonja I
    Ingelsson, Erik
    Willer, Cristen J
    Weedon, Michael N
    Luan, Jian'an
    Vedantam, Sailaja
    Esko, Tõnu
    Kilpeläinen, Tuomas O
    Kutalik, Zoltán
    Li, Shengxu
    Monda, Keri L
    Dixon, Anna L
    Holmes, Christopher C
    Kaplan, Lee M
    Liang, Liming
    Min, Josine L
    Moffatt, Miriam F
    Molony, Cliona
    Nicholson, George
    Schadt, Eric E
    Zondervan, Krina T
    Feitosa, Mary F
    Ferreira, Teresa
    Allen, Hana Lango
    Weyant, Robert J
    Wheeler, Eleanor
    Wood, Andrew R
    Estrada, Karol
    Goddard, Michael E
    Lettre, Guillaume
    Mangino, Massimo
    Nyholt, Dale R
    Purcell, Shaun
    Smith, Albert Vernon
    Visscher, Peter M
    Yang, Jian
    McCarroll, Steven A
    Nemesh, James
    Voight, Benjamin F
    Absher, Devin
    Amin, Najaf
    Aspelund, Thor
    Coin, Lachlan
    Glazer, Nicole L
    Hayward, Caroline
    Heard-Costa, Nancy L
    Hottenga, Jouke-Jan
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Johnson, Toby
    Kaakinen, Marika
    Kapur, Karen
    Ketkar, Shamika
    Knowles, Joshua W
    Kraft, Peter
    Kraja, Aldi T
    Lamina, Claudia
    Leitzmann, Michael F
    McKnight, Barbara
    Morris, Andrew P
    Ong, Ken K
    Perry, John R B
    Peters, Marjolein J
    Polasek, Ozren
    Prokopenko, Inga
    Rayner, Nigel W
    Ripatti, Samuli
    Rivadeneira, Fernando
    Robertson, Neil R
    Sanna, Serena
    Sovio, Ulla
    Surakka, Ida
    Teumer, Alexander
    van Wingerden, Sophie
    Vitart, Veronique
    Zhao, Jing Hua
    Cavalcanti-Proença, Christine
    Chines, Peter S
    Fisher, Eva
    Kulzer, Jennifer R
    Lecoeur, Cecile
    Narisu, Narisu
    Sandholt, Camilla
    Scott, Laura J
    Silander, Kaisa
    Stark, Klaus
    Tammesoo, Mari-Liis
    Teslovich, Tanya M
    Timpson, Nicholas John
    Watanabe, Richard M
    Welch, Ryan
    Chasman, Daniel I
    Cooper, Matthew N
    Jansson, John-Olov
    Kettunen, Johannes
    Lawrence, Robert W
    Pellikka, Niina
    Perola, Markus
    Vandenput, Liesbeth
    Alavere, Helene
    Almgren, Peter
    Atwood, Larry D
    Bennett, Amanda J
    Biffar, Reiner
    Bonnycastle, Lori L
    Bornstein, Stefan R
    Buchanan, Thomas A
    Campbell, Harry
    Day, Ian N M
    Dei, Mariano
    Dörr, Marcus
    Elliott, Paul
    Erdos, Michael R
    Eriksson, Johan G
    Freimer, Nelson B
    Fu, Mao
    Gaget, Stefan
    Geus, Eco J C
    Gjesing, Anette P
    Grallert, Harald
    Grässler, Jürgen
    Groves, Christopher J
    Guiducci, Candace
    Hartikainen, Anna-Liisa
    Hassanali, Neelam
    Havulinna, Aki S
    Herzig, Karl-Heinz
    Hicks, Andrew A
    Hui, Jennie
    Igl, Wilmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jousilahti, Pekka
    Jula, Antti
    Kajantie, Eero
    Kinnunen, Leena
    Kolcic, Ivana
    Koskinen, Seppo
    Kovacs, Peter
    Kroemer, Heyo K
    Krzelj, Vjekoslav
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Laitinen, Jaana
    Lantieri, Olivier
    Lathrop, G Mark
    Lokki, Marja-Liisa
    Luben, Robert N
    Ludwig, Barbara
    McArdle, Wendy L
    McCarthy, Anne
    Morken, Mario A
    Nelis, Mari
    Neville, Matt J
    Paré, Guillaume
    Parker, Alex N
    Peden, John F
    Pichler, Irene
    Pietiläinen, Kirsi H
    Platou, Carl G P
    Pouta, Anneli
    Ridderstråle, Martin
    Samani, Nilesh J
    Saramies, Jouko
    Sinisalo, Juha
    Smit, Jan H
    Strawbridge, Rona J
    Stringham, Heather M
    Swift, Amy J
    Teder-Laving, Maris
    Thomson, Brian
    Usala, Gianluca
    van Meurs, Joyce B J
    van Ommen, Gert-Jan
    Vatin, Vincent
    Volpato, Claudia B
    Wallaschofski, Henri
    Walters, G Bragi
    Widen, Elisabeth
    Wild, Sarah H
    Willemsen, Gonneke
    Witte, Daniel R
    Zgaga, Lina
    Zitting, Paavo
    Beilby, John P
    James, Alan L
    Kähönen, Mika
    Lehtimäki, Terho
    Nieminen, Markku S
    Ohlsson, Claes
    Palmer, Lyle J
    Raitakari, Olli
    Ridker, Paul M
    Stumvoll, Michael
    Tönjes, Anke
    Viikari, Jorma
    Balkau, Beverley
    Ben-Shlomo, Yoav
    Bergman, Richard N
    Boeing, Heiner
    Smith, George Davey
    Ebrahim, Shah
    Froguel, Philippe
    Hansen, Torben
    Hengstenberg, Christian
    Hveem, Kristian
    Isomaa, Bo
    Jørgensen, Torben
    Karpe, Fredrik
    Khaw, Kay-Tee
    Laakso, Markku
    Lawlor, Debbie A
    Marre, Michel
    Meitinger, Thomas
    Metspalu, Andres
    Midthjell, Kristian
    Pedersen, Oluf
    Salomaa, Veikko
    Schwarz, Peter E H
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Valle, Timo T
    Wareham, Nicholas J
    Arnold, Alice M
    Beckmann, Jacques S
    Bergmann, Sven
    Boerwinkle, Eric
    Boomsma, Dorret I
    Caulfield, Mark J
    Collins, Francis S
    Eiriksdottir, Gudny
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamsten, Anders
    Hattersley, Andrew T
    Hofman, Albert
    Hu, Frank B
    Illig, Thomas
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Kao, W H Linda
    Kaprio, Jaakko
    Launer, Lenore J
    Munroe, Patricia B
    Oostra, Ben
    Penninx, Brenda W
    Pramstaller, Peter P
    Psaty, Bruce M
    Quertermous, Thomas
    Rissanen, Aila
    Rudan, Igor
    Shuldiner, Alan R
    Soranzo, Nicole
    Spector, Timothy D
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Uda, Manuela
    Uitterlinden, André
    Völzke, Henry
    Vollenweider, Peter
    Wilson, James F
    Witteman, Jacqueline C
    Wright, Alan F
    Abecasis, Gonçalo R
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Frayling, Timothy M
    Groop, Leif C
    Haritunians, Talin
    Hunter, David J
    Kaplan, Robert C
    North, Kari E
    O'Connell, Jeffrey R
    Peltonen, Leena
    Schlessinger, David
    Strachan, David P
    Hirschhorn, Joel N
    Assimes, Themistocles L
    Wichmann, H-Erich
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M
    Stefansson, Kari
    Cupples, L Adrienne
    Loos, Ruth J F
    Barroso, Inês
    McCarthy, Mark I
    Fox, Caroline S
    Mohlke, Karen L
    Lindgren, Cecilia M
    Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 11, p. 949-960Article in journal (Refereed)
    Abstract [en]

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

  • 105. Hellquist, Anna
    et al.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Zucchelli, Marco
    Koskenmies, Sari
    Julkunen, Heikki
    D'Amato, Mauro
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kere, Juha
    Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 883-886Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    To investigate if 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with SLE in a Swedish case-control cohort, also are associated with SLE risk in a Finnish SLE family cohort.

    METHOD:

    Genotyping was performed in 192 Finnish families, with 237 affected individuals and their healthy relatives, using the SNPstream genotyping system.

    RESULTS:

    TDT analysis provided the strongest signal of association for two linked SNPs; rs7582694 (P-value = 0.002, OR = 2.57) and rs10181656 (P-value = 0.001, OR = 2.53). We further performed haplotype association analysis using a sliding window approach which showed that the strongest association signal originates from SNPs in intron 3 of STAT4.

    CONCLUSION:

    Our results provide evidence that the main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.

  • 106.
    Hibar, Derrek P.
    et al.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA..
    Adams, Hieab H. H.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands..
    Jahanshad, Neda
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA..
    Chauhan, Ganesh
    Univ Bordeaux, INSERM Unit U1219, F-33076 Bordeaux, France..
    Stein, Jason L.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA.;UNC, Dept Genet, Chapel Hill, NC 27599 USA.;UNC, UNC Neurosci Ctr, Chapel Hill, NC 27599 USA..
    Hofer, Edith
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, Auenbruggerpl 22, A-8036 Graz, Austria..
    Renteria, Miguel E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA..
    Arias-Vasquez, Alejandro
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Ikram, M. Kamran
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.;Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore 169857, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore.;Natl Univ Hlth Syst, MACC, Singapore 119228, Singapore.;Natl Univ Singapore, Dept Pharmacol, Singapore 119077, Singapore..
    Desrivieres, Sylvane
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England..
    Vernooij, Meike W.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands..
    Abramovic, Lucija
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Alhusaini, Saud
    McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada.;Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland..
    Amin, Najaf
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands..
    Andersson, Micael
    Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, S-90187 Umea, Sweden..
    Arfanakis, Konstantinos
    IIT, Dept Biomed Engn, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Diagnost Radiol & Nucl Med, Chicago, IL 60616 USA..
    Aribisala, Benjamin S.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Lagos State Univ, Dept Comp Sci, PMB 01 LASU, Lagos, Nigeria.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland..
    Armstrong, Nicola J.
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Murdoch Univ, Math & Stat, Perth, WA 6150, Australia..
    Athanasiu, Lavinia
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Beecham, Ashley H.
    Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Beiser, Alexa
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA..
    Bernard, Manon
    Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada..
    Blanton, Susan H.
    Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA..
    Bohlken, Marc M.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Boks, Marco P.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Bralten, Janita
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Brickman, Adam M.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, GH Sergievsky Ctr, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Neurol, 639 West 1168th St, New York, NY 10032 USA..
    Carmichael, Owen
    Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Chakravarty, M. Mallar
    Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Montreal, PQ H4H 1R3, Canada.;McGill Univ, Dept Psychiat & Biomed Engn, Montreal, PQ H3A 2B4, Canada..
    Chen, Qiang
    Lieber Inst Brain Dev, Baltimore, MD 21205 USA..
    Ching, Christopher R. K.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA.;Univ Calif Los Angeles, Sch Med, Interdept Neurosci Grad Program, Los Angeles, CA 90095 USA..
    Chouraki, Vincent
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA.;Univ Lille, CHU Lille, INSERM, Inst Pasteur Lille,RID AGE Risk Factors & Mol Det, F-59000 Lille, France..
    Cuellar-Partida, Gabriel
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Crivello, Fabrice
    Univ Bordeaux, IMN UMR5293, GIN, CNRS,CEA, 146 Rue Leo Saignat, F-33076 Bordeaux, France..
    Den Braber, Anouk
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    Doan, Nhat Trung
    Ehrlich, Stefan
    Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, D-01307 Dresden, Germany.;Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA..
    Giddaluru, Sudheer
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway.;Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway..
    Goldman, Aaron L.
    Lieber Inst Brain Dev, Baltimore, MD 21205 USA..
    Gottesman, Rebecca F.
    Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA..
    Grimm, Oliver
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Data Sci, D-68159 Mannheim, Germany..
    Griswold, Michael E.
    Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA..
    Guadalupe, Tulio
    Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands.;Int Max Planck Res Sch Language Sci, NL-6525 XD Nijmegen, Netherlands..
    Gutman, Boris A.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA..
    Hass, Johanna
    Tech Univ Dresden, Fac Med, Dept Child & Adolescent Psychiat, D-01307 Dresden, Germany..
    Haukvik, Unn K.
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, N-0319 Oslo, Norway..
    Hoehn, David
    Max Planck Inst Psychiat, D-80804 Munich, Germany..
    Holmes, Avram J.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Yale Univ, Dept Psychol, New Haven, CT 06520 USA..
    Hoogman, Martine
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Janowitz, Deborah
    Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany..
    Jia, Tianye
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England..
    Jorgensen, Kjetil N.
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, N-0319 Oslo, Norway..
    Karbalai, Nazanin
    Max Planck Inst Psychiat, D-80804 Munich, Germany..
    Kasperaviciute, Dalia
    UCL Inst Neurol, London, England.;Epilepsy Soc, St Peter, Bucks, England.;Imperial Coll London, Dept Med, London SW7 2AZ, England..
    Kim, Sungeun
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA..
    Klein, Marieke
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Kraemer, Bernd
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, D-69120 Heidelberg, Germany..
    Lee, Phil H.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA 02141 USA.;Harvard Med Sch, Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA 02421 USA..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Lopez, Lorna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Luciano, Michelle
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Macare, Christine
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England..
    Marquand, Andre F.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands..
    Matarin, Mar
    UCL Inst Neurol, London, England.;Epilepsy Soc, St Peter, Bucks, England.;UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England..
    Mather, Karen A.
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia..
    Mattheisen, Manuel
    Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Aarhus, Denmark.;iPSYCH, Lundbeck Fdn Initiat Integrat Psychiat Res, DK-8000 Copenhagen, Denmark.;Aarhus Univ, iSEQ, Ctr Integrated Sequencing, DK-8000 Aarhus, Denmark..
    McKay, David R.
    Yale Univ, Dept Psychiat, New Haven, CT 06511 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA..
    Milaneschi, Yuri
    VU Univ Med Ctr GGZ inGeest, Dept Psychiat, EMGO Inst Hlth & Care Res, NL-1081 HL Amsterdam, Netherlands.;VU Univ Med Ctr GGZ inGeest, Neurosci Campus Amsterdam, NL-1081 HL Amsterdam, Netherlands..
    Maniega, Susana Munoz
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Nho, Kwangsik
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA..
    Nugent, Allison C.
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA..
    Nyquist, Paul
    Johns Hopkins, Dept Neurol, Dept Anesthesia Crit Care Med, Dept Neurosurg, USA600 N Wolfe St, Baltimore, MD 21287 USA..
    Loohuis, Loes M. Olde
    Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA..
    Oosterlaan, Jaap
    Vrije Univ Amsterdam, Dept Clin Neuropsychol, NL-1081 HV Amsterdam, Netherlands..
    Papmeyer, Martina
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland.;Univ Bern, Univ Hosp Psychiat, Div Syst Neurosci Psychopathol, Translat Res Ctr, CH-3060 Bern, Switzerland..
    Pirpamer, Lukas
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria..
    Puetz, Benno
    Max Planck Inst Psychiat, D-80804 Munich, Germany..
    Ramasamy, Adaikalavan
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England.;Univ Oxford, Jenner Inst Labs, Oxford OX3 7DQ, England..
    Richards, Jennifer S.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, NL-6525 GC Nijmegen, Netherlands..
    Risacher, Shannon L.
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA..
    Roiz-Santianez, Roberto
    Univ Cantabria IDIVAL, Dept Med & Psychiat, Univ Hosp Marques Valdecilla, Sch Med, Santander 39008, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Mental, Santander 39011, Spain..
    Rommelse, Nanda
    Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, NL-6525 GC Nijmegen, Netherlands..
    Ropele, Stefan
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria..
    Rose, Emma J.
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin 2, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin 2, Ireland..
    Royle, Natalie A.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA..
    Saemann, Philipp G.
    Max Planck Inst Psychiat, D-80804 Munich, Germany..
    Saremi, Arvin
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA..
    Satizabal, Claudia L.
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA..
    Schmaal, Lianne
    Orygen, Natl Ctr Excellence Youth Mental Hlth, Melbourne, Vic 3502, Australia.;Univ Melbourne, Ctr Youth Mental Hlth, Melbourne, Vic 3502, Australia.;Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands..
    Schork, Andrew J.
    Univ Calif San Diego, Multimodal Imaging Lab, Dept Neurosci, San Diego, CA 92093 USA.;Univ Calif San Diego, Dept Cognit Sci, San Diego, CA 92161 USA..
    Shen, Li
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA..
    Shin, Jean
    Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada..
    Shumskaya, Elena
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands..
    Smith, Albert V.
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Sprooten, Emma
    Yale Univ, Dept Psychiat, New Haven, CT 06511 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA.;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA..
    Strike, Lachlan T.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany..
    Tordesillas-Gutierrez, Diana
    CIBERSAM Ctr Invest Biomed Red Salud Mental, Santander 39011, Spain.;Valdecilla Biomed Res Inst IDIVAL, Neuroimaging Unit, Technol Facilities, Santander 39011, Cantabria, Spain..
    Toro, Roberto
    Inst Pasteur, F-75015 Paris, France..
    Trabzuni, Daniah
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Vaidya, Dhananjay
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, 1830 Monument St Suite 8028, Baltimore, MD 21287 USA..
    Van der Grond, Jeroen
    Leiden Univ, Med Ctr, Dept Radiol, NL-2300 RC Leiden, Netherlands..
    Van der Lee, Sven J.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands..
    van der Meer, Dennis
    Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands..
    Van Donkelaar, Marjolein M. J.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Van Eijk, Kristel R.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Human Neurogenet Unit, NL-3584 CG Utrecht, Netherlands..
    Van Erp, Theo G. M.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA..
    Van Rooij, Daan
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands..
    Walton, Esther
    Tech Univ Dresden, Fac Med, Div Psychol & Social Med & Dev Neurosci, D-01307 Dresden, Germany.;Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA..
    Westlye, Lars T.
    Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway.;Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA..
    Whelan, Christopher D.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA.;Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland..
    Windham, Beverly G.
    Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, N-0317 Oslo, Norway..
    Winkler, Anderson M.
    Yale Univ, Dept Psychiat, New Haven, CT 06511 USA.;Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Wittfeld, Katharina
    Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany.;Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England..
    Woldehawariat, Girma
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA..
    Wolf, Christiane
    German Ctr Neurodegenerat Dis DZNE Rostock Greifs, D-17487 Greifswald, Germany..
    Wolfers, Thomas
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, 1830 Monument St Suite 8028, Baltimore, MD 21287 USA..
    Yang, Jingyun
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97080 Wurzburg, Germany..
    Zijdenbos, Alex
    Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Zwiers, Marcel P.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands..
    Agartz, Ingrid
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Diakonhjemmet Hosp, Dept Res & Dev, N-0319 Oslo, Norway.;Biospective Inc, 6100 Ave Royalmount, Montreal, PQ H4P 2R2, Canada..
    Almasy, Laura
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden.;Univ Texas Brownsville, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX 78250 USA.;Univ Texas, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, Edinburg, TX 78250 USA.;Univ Texas San Antonio, Rio Grande Valley Sch Med, South Texas Diabet & Obes Inst, San Antonio, TX 78250 USA.;Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Ames, David
    Childrens Hosp Philadelphia, Dept Biomed & Hlth Informat, Philadelphia, PA 19104 USA.;Royal Melbourne Hosp, Natl Ageing Res Inst, Parkville, Vic 3052, Australia..
    Amouyel, Philippe
    Univ Lille, CHU Lille, INSERM, Inst Pasteur Lille,RID AGE Risk Factors & Mol Det, F-59000 Lille, France..
    Andreassen, Ole A.
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway..
    Arepalli, Sampath
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Assareh, Amelia A.
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia..
    Barral, Sandra
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, GH Sergievsky Ctr, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Neurol, 639 West 1168th St, New York, NY 10032 USA..
    Bastin, Mark E.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, GeneSTAR Res Ctr, 1830 Monument St Suite 8028, Baltimore, MD 21287 USA..
    Becker, James T.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Bennett, David A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, D-97080 Wurzburg, Germany..
    Blangero, John
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden..
    van Bokhoven, Hans
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    Brodaty, Henry
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Univ Pittsburgh, Dept Psychiat, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA.;Univ Pittsburgh, Dept Neurol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA.;Univ Pittsburgh, Dept Psychol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA..
    Brouwer, Rachel M.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Brunner, Han G.
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Univ New South Wales, Dementia Collaborat Res Centre Assessment & Bette, Sydney, NSW 2052, Australia..
    Buckner, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands.;Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, NL-6200 MD Maastricht, Netherlands..
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Karakter Child & Adolescent Psychiat Univ Ctr, NL-6525 GC Nijmegen, Netherlands..
    Bulayeva, Kazima B.
    Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA..
    Cahn, Wiepke
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Calhoun, Vince D.
    Dagestan State Univ, Dept Evolut & Genet, Makhachkala 367000, Dagestan, Russia.;Mind Res Network, Albuquerque, NM 87106 USA.;LBERI, Albuquerque, NM 87106 USA..
    Cannon, Dara M.
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA.;Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA..
    Cavalleri, Gianpiero L.
    Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland..
    Cheng, Ching-Yu
    Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore 169857, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore.;Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, Clin Neuroimaging Lab, NCBES Galway Neurosci Ctr,Coll Med Nursing & Hlth, Galway H91 TK33, Ireland..
    Cichon, Sven
    Natl Univ Singapore, Dept Ophthalmol, Yong Loo Lin Sch Med, Singapore 119077, Singapore.;Univ Basel, Dept Biome, Div Med Genet, CH-4031 Basel, Switzerland.;Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany..
    Cookson, Mark R.
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Corvin, Aiden
    Trinity Coll Dublin, Psychosis Res Grp, Dept Psychiat, Dublin 2, Ireland.;Trinity Coll Dublin, Trinity Translat Med Inst, Dublin 2, Ireland..
    Crespo-Facorro, Benedicto
    Univ Cantabria IDIVAL, Dept Med & Psychiat, Univ Hosp Marques Valdecilla, Sch Med, Santander 39008, Spain.;CIBERSAM Ctr Invest Biomed Red Salud Mental, Santander 39011, Spain..
    Curran, Joanne E.
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden..
    Czisch, Michael
    Max Planck Inst Psychiat, D-80804 Munich, Germany..
    Dale, Anders M.
    Res Ctr Julich, Inst Neurosci & Med INM 1, D-52425 Julich, Germany.;Univ Calif San Diego, Ctr Multimodal Imaging & Genet, San Diego, CA 92093 USA..
    Davies, Gareth E.
    Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.;Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA.;Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.;Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA..
    De Craen, Anton J. M.
    Avera Inst Human Genet, Sioux Falls, SD 57108 USA..
    De Geus, Eco J. C.
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    De Jager, Philip L.
    Natl Univ Singapore, Dept Pharmacol, Singapore 119077, Singapore.;Harvard Med Sch, Boston, MA 02115 USA.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands.;Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Neurol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Program Translat NeuroPsychiat Gen, Dept Psychiat, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    De Zubicaray, Greig I.
    Broad Inst, Cambridge, MA 02142 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Debette, Stephanie
    Univ Bordeaux, INSERM Unit U1219, F-33076 Bordeaux, France.;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Queensland Univ Technol, Fac Hlth & Inst Hlth & Biomed Innovat, Brisbane, Qld 4059, Australia..
    DeCarli, Charles
    Bordeaux Univ Hosp, Dept Neurol, F-33076 Bordeaux, France..
    Delanty, Norman
    Royal Coll Surgeons Ireland, 123 St Stephens Green, Dublin 2, Ireland.;Univ Calif Davis, Imaging Dementia & Aging IDeA Lab, Dept Neurol, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA.;Univ Calif Davis, Ctr Neurosci, 4860 Y St,Suite 3700, Sacramento, CA 95817 USA..
    Depondt, Chantal
    Beaumont Hosp, Div Neurol, Dublin 9, Ireland..
    DeStefano, Anita
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA..
    Dillman, Allissa
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Djurovic, Srdjan
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway.;Univ Libre Bruxelles, Dept Neurol, Hop Erasme, B-1070 Brussels, Belgium..
    Donohoe, Gary
    Oslo Univ Hosp, Dept Med Genet, N-0420 Oslo, Norway.;Natl Univ Ireland Galway, Cognit Genet & Cognit Therapy Grp, Neuroimaging Cognit & Genom Ctr NICOG, Sch Psychol & Discipline Biochem, Galway H91 TK33, Ireland.;Natl Univ Ireland Galway, Sch Psychol & Discipline Biochem, NCBES Galway Neurosci Ctr, Galway H91 TK33, Ireland..
    Drevets, Wayne C.
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA.;Trinity Coll Dublin, Neuropsychiat Genet Res Grp, Dept Psychiat, Dublin 8, Ireland.;Trinity Coll Dublin, Trinity Coll, Inst Psychiat, Dublin 8, Ireland..
    Duggirala, Ravi
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden..
    Dyer, Thomas D.
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden..
    Enzinger, Christian
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria..
    Erk, Susanne
    Janssen Res & Dev LLC, Titusville, NJ 08560 USA..
    Espeseth, Thomas
    Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway.;Georgia State Univ, Dept Psychol, Atlanta, GA 30302 USA..
    Fedko, Iryna O.
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    Fernandez, Guillen
    Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neurosci, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Ferrucci, Luigi
    Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte,Charite Pl 1, D-10117 Berlin, Germany..
    Fisher, Simon E.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands..
    Fleischman, Debra A.
    Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA.;NIA, Intramural Res Program, Baltimore, MD 21224 USA..
    Ford, Ian
    Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60616 USA.;Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60616 USA..
    Fornage, Myriam
    Univ Glasgow, Robertson Ctr Biostat, Glasgow G41 4DQ, Lanark, Scotland..
    Foroud, Tatiana M.
    Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA.;Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA..
    Fox, Peter T.
    Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA..
    Francks, Clyde
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands.;Max Planck Inst Psycholinguist, Language & Genet Dept, NL-6525 XD Nijmegen, Netherlands..
    Fukunaga, Masaki
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Gibbs, J. Raphael
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Glahn, David C.
    Yale Univ, Dept Psychiat, New Haven, CT 06511 USA.;Olin Neuropsychiat Res Ctr, Hartford, CT 06114 USA..
    Gollub, Randy L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Goring, Harald H. H.
    Karolinska Inst, Dept Clin Neurosci, Ctr Psychiat Res, SE-17177 Stockholm, Sweden..
    Green, Robert C.
    Harvard Med Sch, Boston, MA 02115 USA.;Natl Inst Physiol Sci, Div Cerebral Integrat, Okazaki, Aichi 4448585, Japan..
    Gruber, Oliver
    Heidelberg Univ, Dept Gen Psychiat, Sect Expt Psychopathol & Neuroimaging, D-69120 Heidelberg, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Guelfi, Sebastian
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England..
    Haberg, Asta K.
    Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA.;Norwegian Univ Sci & Technol NTNU, Fac Med, Dept Neurosci, N-7491 Trondheim, Norway..
    Hansell, Narelle K.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia..
    Hardy, John
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England..
    Hartman, Catharina A.
    Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands..
    Hashimoto, Ryota
    Univ Trondheim Hosp, Dept Radiol, St Olavs Hosp, N-7030 Trondheim, Norway.;Osaka Univ, Dept Psychiat, Grad Sch Med, Suita, Osaka 5650871, Japan..
    Hegenscheid, Katrin
    Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka 5650871, Japan..
    Heinz, Andreas
    Janssen Res & Dev LLC, Titusville, NJ 08560 USA..
    Le Hellard, Stephanie
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway.;Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway..
    Hernandez, Dena G.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.;UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia.;Univ Med Greifswald, Inst Diagnost Radiol & Neuroradiol, D-17489 Greifswald, Germany..
    Heslenfeld, Dirk J.
    German Ctr Neurodegenerat Dis DZNE, D-72076 Tubingen, Germany..
    Ho, Beng-Choon
    Vrije Univ Amsterdam, Dept Psychol, NL-1081 BT Amsterdam, Netherlands..
    Hoekstra, Pieter J.
    Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands..
    Hoffmann, Wolfgang
    Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany.;Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England..
    Hofman, Albert
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Holsboer, Florian
    Max Planck Inst Psychiat, D-80804 Munich, Germany.;Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA..
    Homuth, Georg
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Hosten, Norbert
    Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Suita, Osaka 5650871, Japan..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    Huentelman, Matthew
    HMNC Brain Hlth, D-80539 Munich, Germany..
    Pol, Hilleke E. Hulshoff
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Ikeda, Masashi
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, D-17489 Greifswald, Germany..
    Jack, Clifford R., Jr.
    Translat Genom Res Inst, Neurogen Div, 445N Fifth St, Phoenix, AZ 85004 USA..
    Jenkinson, Mark
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Johnson, Robert
    Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan..
    Joensson, Erik G.
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Biospective Inc, 6100 Ave Royalmount, Montreal, PQ H4P 2R2, Canada..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Kahn, Rene S.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    Kanai, Ryota
    Mayo Clin, Dept Radiol, Rochester, MN 55905 USA.;Univ Maryland, Sch Med, NICHD Brain & Tissue Bank Dev Disorders, Baltimore, MD 21201 USA.;Univ Sussex, Sch Psychol, Brighton BN1 9QH, E Sussex, England..
    Kloszewska, Iwona
    UCL, Inst Cognit Neurosci, London WC1N 3AR, England..
    Knopman, David S.
    Araya Brain Imaging, Dept Neuroinformat, Tokyo 1020093, Japan..
    Kochunov, Peter
    Med Univ Lodz, PL-90419 Lodz, Poland..
    Kwok, John B.
    Mayo Clin, Dept Neurol, Rochester, MN 55905 USA.;Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA..
    Lawrie, Stephen M.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland..
    Lemaitre, Herve
    Neurosci Res Australia, Randwick, NSW 2031, Australia..
    Liu, Xinmin
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA.;UNSW, Sch Med Sci, Sydney, NSW 2052, Australia..
    Longo, Dan L.
    Univ Paris 05, Univ Paris Saclay, INSERM UMR Neuroimaging & Psychiat 1000, Serv Hosp Freric Joliot,Univ Paris Sud,Maison Sol, F-91400 Orsay, France..
    Lopez, Oscar L.
    Columbia Univ, Med Ctr, New York, NY 10032 USA..
    Lovestone, Simon
    NIA, Genet Lab, NIH, Baltimore, MD 21224 USA.;Univ Pittsburgh, Dept Neurol, 3501 Forbes Ave,Suite 830, Pittsburgh, PA 15213 USA..
    Martinez, Oliver
    Bordeaux Univ Hosp, Dept Neurol, F-33076 Bordeaux, France..
    Martinot, Jean-Luc
    Neurosci Res Australia, Randwick, NSW 2031, Australia..
    Mattay, Venkata S.
    Lieber Inst Brain Dev, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA.;Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England..
    McDonald, Colm
    Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA..
    McIntosh, Andrew M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland..
    McMahon, Francis J.
    NIMH, Human Genet Branch, Intramural Res Program, 35 Convent Dr,Rm 1A202, Bethesda, MD 20892 USA..
    McMahon, Katie L.
    Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA..
    Mecocci, Patrizia
    Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia..
    Melle, Ingrid
    Univ Oslo, NORMENT KG Jebsen Ctr, Inst Clin Med, N-0315 Oslo, Norway.;Oslo Univ Hosp, NORMENT KG Jebsen Ctr, Div Mental Hlth & Addict, N-0424 Oslo, Norway..
    Meyer-Lindenberg, Andreas
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Data Sci, D-68159 Mannheim, Germany..
    Mohnke, Sebastian
    Janssen Res & Dev LLC, Titusville, NJ 08560 USA..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Morris, Derek W.
    Oslo Univ Hosp, Dept Med Genet, N-0420 Oslo, Norway..
    Mosley, Thomas H.
    Univ Oslo, Dept Psychol, NORMENT KG Jebsen Ctr, N-0317 Oslo, Norway..
    Muhleisen, Thomas W.
    Univ Basel, Dept Biome, Div Med Genet, CH-4031 Basel, Switzerland.;Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany..
    Mueller-Myhsok, Bertram
    Max Planck Inst Psychiat, D-80804 Munich, Germany.;Univ Perugia, Dept Med, Sect Gerontol & Geriatr, I-06132 Perugia, Italy.;Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany..
    Nalls, Michael A.
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Nauck, Matthias
    Univ Liverpool, Inst Translat Med, Liverpool L69 3BX, Merseyside, England.;Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany..
    Nichols, Thomas E.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.;German Ctr Cardiovascular Res DZHK eV, Partner Site Greifswald, D-17475 Greifswald, Germany..
    Niessen, Wiro J.
    Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands.;Univ Warwick, Dept Stat, Coventry CV4 7AL, W Midlands, England.;Univ Warwick, WMG, Coventry CV4 7AL, W Midlands, England.;Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands..
    Nothen, Markus M.
    Univ Basel, Dept Biome, Div Med Genet, CH-4031 Basel, Switzerland.;Delft Univ Technol, Fac Sci Appl, NL-2628 CD Delft, Netherlands..
    Nyberg, Lars
    Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging, S-90187 Umea, Sweden..
    Ohi, Kazutaka
    Univ Trondheim Hosp, Dept Radiol, St Olavs Hosp, N-7030 Trondheim, Norway..
    Olvera, Rene L.
    Indiana Univ Sch Med, Med & Mol Genet, Indianapolis, IN 46202 USA..
    Ophoff, Roel A.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands.;Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA..
    Pandolfo, Massimo
    Beaumont Hosp, Div Neurol, Dublin 9, Ireland..
    Paus, Tomas
    Univ Bonn, Dept Gen, Life & Brain Ctr, D-53127 Bonn, Germany.;Univ Toronto, Rotman Res Inst, Toronto, ON M6A 2E1, Canada.;Univ Toronto, Dept Psychol, Toronto, ON M5T 1R8, Canada.;Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada..
    Pausova, Zdenka
    Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada.;Child Mind Inst, New York, NY 10022 USA..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands..
    Pike, G. Bruce
    Univ Toronto, Dept Physiol, Toronto, ON M5S 3E2, Canada.;Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada.;Univ Calgary, Dept Radiol, Calgary, AB T2N 4N1, Canada..
    Potkin, Steven G.
    Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA..
    Psaty, Bruce M.
    Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada..
    Reppermund, Simone
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;USA Grp Hlth Res Inst, Grp Hlth, 1730 Minor Ave Suite 1360, Seattle, WA 98101 USA..
    Rietschel, Marcella
    Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Data Sci, D-68159 Mannheim, Germany..
    Roffman, Joshua L.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA..
    Romanczuk-Seiferth, Nina
    Janssen Res & Dev LLC, Titusville, NJ 08560 USA..
    Rotter, Jerome I.
    Univ New South Wales, Dept Dev Disabil Neuropsychiat, Sch Psychiat, Sydney, NSW 2052, Australia..
    Ryten, Mina
    UCL Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England.;UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat, Torrance, CA 90502 USA..
    Sachdev, Perminder S.
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Saykin, Andrew J.
    Indiana Univ Sch Med, Ctr Neuroimaging Radiol & Imaging Sci, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA.;Univ Texas Hlth Sci Ctr Houston, Inst Mol Med & Human Genet Ctr, Houston, TX 77030 USA..
    Schmidt, Reinhold
    Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Auenbruggerpl 22, A-8036 Graz, Austria..
    Schmidt, Helena
    Prince Wales Hosp, Neuropsychiat Inst, Randwick, NSW 2031, Australia..
    Schofield, Peter R.
    Mayo Clin, Dept Neurol, Rochester, MN 55905 USA.;Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA..
    Sigursson, Sigurdur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland..
    Simmons, Andrew
    Med Univ Graz, Inst Mol Biol & Biochem, Harrachgasse 21-3, A-8010 Graz, Austria.;Kings Coll London, Inst Psychiat, Dept Neuroimaging, London SE5 8AF, England.;Kings Coll London, Biomed Res Ctr Mental Hlth, London SE5 8AF, England..
    Singleton, Andrew
    Sisodiya, Sanjay M.
    UCL Inst Neurol, London, England.;Epilepsy Soc, St Peter, Bucks, England..
    Smith, Colin
    Kings Coll London, Biomed Res Unit Dementia, London SE5 8AF, England..
    Smoller, Jordan W.
    Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Boston, MA 02141 USA..
    Soininen, Hilkka
    Univ Edinburgh, Acad Dept Neuropathol, Ctr Clin Brain Sci, MRC Edinburgh Brain Bank, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Eastern Finland, Inst Clin Med, Neurol, FI-70211 Kuopio, Finland..
    Steen, Vidar M.
    Univ Bergen, Dept Clin Sci, NORMENT KG Jebsen Ctr Psychosis Res, N-5021 Bergen, Norway.;Haukeland Hosp, Dr Einar Martens Res Grp Biol Psychiat, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway..
    Stott, David J.
    Kuopio Univ Hosp, Neuroctr Neurol, FI-70211 Kuopio, Finland..
    Sussmann, Jessika E.
    Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland..
    Thalamuthu, Anbupalam
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia..
    Toga, Arthur W.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow G4 0SF, Lanark, Scotland..
    Traynor, Bryan J.
    Univ Melbourne, Acad Unit Psychiat Old Age, Melbourne, Vic 3101, Australia..
    Troncoso, Juan
    Univ Southern Calif, Lab Neuro Imaging, Inst Neuroimaging & Informat, Keck Sch Med, Los Angeles, CA 90033 USA..
    Tsolaki, Magda
    Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA..
    Tzourio, Christophe
    Univ Bordeaux, INSERM Unit U1219, F-33076 Bordeaux, France.;Aristotle Univ Thessaloniki, Dept Neurol 3, G Papanicolaou Hosp, Thessaloniki 57010, Greece..
    Uitterlinden, Andre G.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.;Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, UMR1219, F-33000 Bordeaux, France..
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    Erasmus MC, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands..
    van der Lugt, Aad
    Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands..
    van der Wee, Nic J. A.
    Genentech Inc, San Francisco, CA 94080 USA..
    Van Haren, Neeltje E. M.
    UMC Utrecht, Brain Ctr Rudolf Magnus, Dept Psychiat, NL-3584 CX Utrecht, Netherlands..
    van't Ent, Dennis
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam Neurosci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 BT Amsterdam, Netherlands..
    Van Tol, Marie-Jose
    Leiden Univ, Med Ctr, Dept Psychiat, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Med Ctr, Leiden Inst Brain & Cognit, NL-2333 ZA Leiden, Netherlands..
    Vardarajan, Badri N.
    Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, GH Sergievsky Ctr, 639 West 1168th St, New York, NY 10032 USA.;Columbia Univ, Med Ctr, Dept Neurol, 639 West 1168th St, New York, NY 10032 USA..
    Vellas, Bruno
    Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, NL-9713 AW Groningen, Netherlands..
    Veltman, Dick J.
    Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, NL-1007 MB Amsterdam, Netherlands..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, D-17489 Greifswald, Germany..
    Walter, Henrik
    Janssen Res & Dev LLC, Titusville, NJ 08560 USA..
    Wardlaw, Joanna M.
    Univ Edinburgh, Brain Res Imaging Ctr, Edinburgh EH4 2XU, Midlothian, Scotland.;Univ Edinburgh, Dept Neuroimaging Sci, Scottish Imaging Network, Platform Sci Excellence SINAPSE Collaborat, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Wassink, Thomas H.
    Univ Toulouse, Dept Internal Med & Geriatr Med, INSERM U1027, F-31024 Toulouse, France..
    Weale, Michael E.
    Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England..
    Weinberger, Daniel R.
    Lieber Inst Brain Dev, Baltimore, MD 21205 USA.;Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA..
    Weiner, Michael W.
    Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA.;Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA..
    Wen, Wei
    Univ New South Wales, Ctr Healthy Brain Ageing, Sch Psychiat, Sydney, NSW 2052, Australia.;Univ Miami, Miller Sch Med, Evelyn F McKnight Brain Inst, Miami, FL 33136 USA..
    Westman, Eric
    Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, San Francisco VA Med Ctr, San Francisco, CA 94121 USA..
    White, Tonya
    Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands.;Karolinska Inst, Dept Neurobiol, Care Sci & Soc, SE-14157 Huddinge, Sweden..
    Wong, Tien Y.
    Duke NUS Grad Med Sch, Acad Med Res Inst, Singapore 169857, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore 168751, Singapore.;Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom NICOG, Clin Neuroimaging Lab, NCBES Galway Neurosci Ctr,Coll Med Nursing & Hlth, Galway H91 TK33, Ireland..
    Wright, Clinton B.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA.;Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth Sci, Miami, FL 33136 USA.;Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst & Pediat, Torrance, CA 90502 USA..
    Zielke, Ronald H.
    Fujita Hlth Univ, Sch Med, Dept Psychiat, Toyoake, Aichi 4701192, Japan..
    Zonderman, Alan B.
    Erasmus MC Sophia Childrens Hosp, Dept Child & Adolescent Psychiat Psychol, NL-3015 CE Rotterdam, Netherlands..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Van Duijn, Cornelia M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands..
    Wright, Margaret J.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia.;Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA..
    Longstreth, W. T.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA..
    Schumann, Gunter
    Kings Coll London, MRC SGDP Ctr, Inst Psychiat Psychol & Neurosci, London SE5 8AF, England..
    Grabe, Hans J.
    Univ Med Greifswald, Dept Psychiat, D-17489 Greifswald, Germany..
    Franke, Barbara
    Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 GA Nijmegen, Netherlands.;Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 GA Nijmegen, Netherlands..
    Launer, Lenore J.
    Univ Washington, Dept Neurol, 325 Ninth Ave, Washington, DC 98104 USA.;Univ Washington, Dept Epidemiol, 325 Ninth Ave, Seattle, WA 98104 USA..
    Medland, Sarah E.
    QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia..
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 17 Mt Wayte Ave, Framingham, MA 01703 USA..
    Thompson, Paul M.
    Univ Southern Calif, Imaging Genet Ctr, USC Mark & Mary Stevens Neuroimaging & Informat I, Keck Sch Med, Marina Del Rey, CA 90292 USA..
    Ikram, M. Arfan
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3015 CE Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, NL-3015 CE Rotterdam, Netherlands.;NIA, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Erasmus MC, Dept Neurol, NL-3015 CE Rotterdam, Netherlands..
    Novel genetic loci associated with hippocampal volume2017In: Nature Communications, E-ISSN 2041-1723, Vol. 8, article id 13624Article in journal (Refereed)
    Abstract [en]

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

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  • 107. Hom, Geoffrey
    et al.
    Graham, Robert R
    Modrek, Barmak
    Taylor, Kimberly E
    Ortmann, Ward
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lee, Annette T
    Chung, Sharon A
    Ferreira, Ricardo C
    Pant, P V Krishna
    Ballinger, Dennis G
    Kosoy, Roman
    Demirci, F Yesim
    Kamboh, M Ilyas
    Kao, Amy H
    Tian, Chao
    Gunnarsson, Iva
    Bengtsson, Anders A
    Rantapää-Dahlqvist, Solbritt
    Petri, Michelle
    Manzi, Susan
    Seldin, Michael F
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Criswell, Lindsey A
    Gregersen, Peter K
    Behrens, Timothy W
    Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 358, no 9, p. 900-909Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.

    METHODS:

    We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.

    RESULTS:

    Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1×10−10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3×10−11).

    CONCLUSIONS:

    We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM-ITGAX region.

  • 108. Hruby, Adela
    et al.
    Ngwa, Julius S.
    Renstrom, Frida
    Wojczynski, Mary K.
    Ganna, Andrea
    Hallmans, Goran
    Houston, Denise K.
    Jacques, Paul F.
    Kanoni, Stavroula
    Lehtimaki, Terho
    Lemaitre, Rozenn N.
    Manichaikul, Ani
    North, Kari E.
    Ntalla, Ioanna
    Sonestedt, Emily
    Tanaka, Toshiko
    van Rooij, Frank J. A.
    Bandinelli, Stefania
    Djousse, Luc
    Grigoriou, Efi.
    Johansson, Ingegerd
    Lohman, Kurt K.
    Pankow, James S.
    Raitakari, Olli T.
    Riserus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Yannakoulia, Mary
    Zillikens, M. Carola
    Hassanali, Neelam
    Liu, Yongmei
    Mozaffarian, Dariush
    Papoutsakis, Constantina
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Uitterlinden, Andre G.
    Viikari, Jorma
    Groves, Christopher J.
    Hofman, Albert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    McCarthy, Mark I.
    Mikkila, Vera
    Mukamal, Kenneth
    Franco, Oscar H.
    Borecki, Ingrid B.
    Cupples, L. Adrienne
    Dedoussis, George V.
    Ferrucci, Luigi
    Hu, Frank B.
    Ingelsson, Erik
    Kahonen, Mika
    Kao, W. H. Linda
    Kritchevsky, Stephen B.
    Orho-Melander, Marju
    Prokopenko, Inga
    Rotter, Jerome I.
    Siscovick, David S.
    Witteman, Jacqueline C. M.
    Franks, Paul W.
    Meigs, James B.
    McKeown, Nicola M.
    Nettleton, Jennifer A.
    Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies2013In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 143, no 3, p. 345-353Article in journal (Refereed)
    Abstract [en]

    Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (In-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [beta = -0.009 mmol/L (95% CI: -0.013, -0.005), P< 0.0001] and insulin (-0.020 In-pmo/L (95% CI: -0.024, -0.017), P< 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P= 0.03) with glucose, and rs11558471 in SLC30A8and rs3740393 near CNNM2showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

  • 109. Huang, Jie
    et al.
    Sabater-Lleal, Maria
    Asselbergs, Folkert W
    Tregouet, David
    Shin, So-Youn
    Ding, Jingzhong
    Baumert, Jens
    Oudot-Mellakh, Tiphaine
    Folkersen, Lasse
    Johnson, Andrew D
    Smith, Nicholas L
    Williams, Scott M
    Ikram, Mohammad A
    Kleber, Marcus E
    Becker, Diane M
    Truong, Vinh
    Mychaleckyj, Josyf C
    Tang, Weihong
    Yang, Qiong
    Sennblad, Bengt
    Moore, Jason H
    Williams, Frances M K
    Dehghan, Abbas
    Silbernagel, Günther
    Schrijvers, Elisabeth M C
    Smith, Shelly
    Karakas, Mahir
    Tofler, Geoffrey H
    Silveira, Angela
    Navis, Gerjan J
    Lohman, Kurt
    Chen, Ming-Huei
    Peters, Annette
    Goel, Anuj
    Hopewell, Jemma C
    Chambers, John C
    Saleheen, Danish
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Psaty, Bruce M
    Strawbridge, Rona J
    Boehm, Bernhard O
    Carter, Angela M
    Meisinger, Christa
    Peden, John F
    Bis, Joshua C
    McKnight, Barbara
    Ohrvik, John
    Taylor, Kent
    Franzosi, Maria Grazia
    Seedorf, Udo
    Collins, Rory
    Franco-Cereceda, Anders
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Goodall, Alison H
    Yanek, Lisa R
    Cushman, Mary
    Müller-Nurasyid, Martina
    Folsom, Aaron R
    Basu, Saonli
    Matijevic, Nena
    van Gilst, Wiek H
    Kooner, Jaspal S
    Hofman, Albert
    Danesh, John
    Clarke, Robert
    Meigs, James B
    Kathiresan, Sekar
    Reilly, Muredach P
    Klopp, Norman
    Harris, Tamara B
    Winkelmann, Bernhard R
    Grant, Peter J
    Hillege, Hans L
    Watkins, Hugh
    Spector, Timothy D
    Becker, Lewis C
    Tracy, Russell P
    März, Winfried
    Uitterlinden, Andre G
    Eriksson, Per
    Cambien, Francois
    Morange, Pierre-Emmanuel
    Koenig, Wolfgang
    Soranzo, Nicole
    van der Harst, Pim
    Liu, Yongmei
    O'Donnell, Christopher J
    Hamsten, Anders
    Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 24, p. 4873-81Article in journal (Refereed)
    Abstract [en]

    We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

  • 110.
    Hägg, Sara
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ploner, Alexander
    Maegi, Reedik
    Fischer, Krista
    Draisma, Harmen H. M.
    Kals, Mart
    de Vries, Paul S.
    Dehghan, Abbas
    Willems, Sara M.
    Sarin, Antti-Pekka
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Havulinna, Aki S.
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Kuningas, Maris
    Stricker, Bruno H.
    Franco, Oscar H.
    Benyamin, Beben
    Gieger, Christian
    Hall, Alistair S.
    Huikari, Ville
    Jula, Antti
    Jarvelin, Marjo-Riitta
    Kaakinen, Marika
    Kaprio, Jaakko
    Kobl, Michael
    Mangino, Massimo
    Nelson, Christopher P.
    Palotie, Aarno
    Samani, Nilesh J.
    Spector, Tim D.
    Strachan, David P.
    Tobin, Martin D.
    Whitfield, John B.
    Uitterlinden, Andre G.
    Salomaa, Veikko
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kuulasmaa, Kari
    Magnusson, Patrik K.
    Esko, Tonu
    Hofman, Albert
    de Geus, Eco J. C.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Gianfagna, Francesco
    Brambilla, Paolo
    Ripatti, Samuli
    van Duijn, Cornelia M.
    Metspalu, Andres
    Prokopenko, Inga
    McCarthy, Mark I.
    Pedersen, Nancy L.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Adiposity as a cause of cardiovascular disease: a Mendelian randomization study2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 2, p. 578-586Article in journal (Refereed)
    Abstract [en]

    Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

  • 111.
    Höglund, Jacob
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Population Biology.
    Wang, Biao
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Population Biology.
    Axelsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Quintela, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Population Biology.
    Phylogeography of willow grouse (Lagopus lagopus) in the Arctic: taxonomic discordance as inferred from molecular data2013In: Biological Journal of the Linnean Society, ISSN 0024-4066, E-ISSN 1095-8312, Vol. 110, no 1, p. 77-90Article in journal (Refereed)
    Abstract [en]

    Using independently segregating nuclear single nucleotide polymorphisms (SNPs) and mitochondrial control region sequences, we found an east-west division among sampled willow grouse Lagopus lagopus subspecies. This division cut across the range of the subspecies with the largest distribution (lagopus) and thus contradicted existing taxonomic classifications. Russian Lagopus lagopus lagopus tended to cluster with North American willow grouse partly classified as other subspecies. Scandinavian willow grouse (L.l. lagopus) clustered with red grouse from Britain and Ireland (Lagopus lagopus scoticus and Lagopus lagopus hibernicus) but substructuring confirmed the monophyly of the latter. In North America, we could not detect any major genetic divisions apart from two birds described as alexandrae from the Heceta Island (Alaska) when using mitochondrial sequences. Other samples from North America were intermingled regardless of whether they were described as muriei, alexandrae or lagopus. A specimen described as alexandrae was to some extent distinct when analysing the SNP data. The genetic analyses indicated some concordance between genetics and taxonomy but not complete congruence. This is particularly evident for mitochondrial DNA network analyses. We suggest that the taxonomy of this species would benefit by a careful re-examination of the available evidence for subspecies. It appears as if subspecies status is a poor proxy for assigning evolutionary significant units and management units in this species.

  • 112.
    Idborg, Helena
    et al.
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Zandian, Arash
    SciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden..
    Ossipova, Elena
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Wigren, Edvard
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Preger, Charlotta
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Mobarrez, Fariborz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Checa, Antonio
    Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden..
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Pucholt, Pascal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Fernandes-Cerqueira, Cátia
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Oke, Vilija
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Grosso, Giorgia
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Kvarnström, Marika
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wheelock, Craig E
    Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Persson, Helena
    Science for Life Laboratory, Drug Discovery and Development & School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden..
    Gräslund, Susanne
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Gunnarsson, Iva
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Nilsson, Peter
    SciLifeLab, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden..
    Svenungsson, Elisabet
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Jakobsson, Per-Johan
    Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden..
    Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed)
    Abstract [en]

    Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10-9, 3 × 10-6, and 5 × 10-6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

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  • 113.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Epigenetic and Gene Expression Signatures in Systemic Inflammatory Autoimmune Diseases2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autoimmune diseases are clinical manifestations of a loss-of-tolerance of the immune system against the body’s own substances and healthy tissues. Primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) are two chronic inflammatory autoimmune diseases characterized by autoantibody production and an activated type I interferon system. Although the precise mechanisms leading to autoimmune processes are not well defined, recent studies suggest that aberrant DNA methylation and gene expression patterns may play a central role in the pathogenesis of these disorders. The aim of this thesis was to investigate DNA methylation and gene expression in pSS and SLE on a genome-wide scale to advance our understanding of how these factors contribute to the diseases and to identify potential biomarkers and novel treatment targets.

    In study I, differential DNA methylation was analyzed in multiple tissues from pSS patients and healthy controls. We identified thousands of CpG sites with perturbed methylation; the most prominent finding was a profound hypomethylation at regulatory regions of type I interferon induced genes in pSS. In study II, a cases-case study comparing DNA methylation in pSS patients with high fatigue to patients with low fatigue, we found methylation patterns associated to the degree of fatigue. In study III, RNA-sequencing was applied to investigate the transcriptome of B cells in pSS in comparison to controls. Increased expression of type I and type II interferon regulated genes in pSS was observed, indicating ongoing immune activation in B cells. In study IV, the impact of DNA methylation on disease susceptibility and phenotypic variability in SLE was investigated. We identified DNA methylation patterns associated to disease susceptibility, SLE manifestations and different treatments. In addition, we mapped methylation quantitative trait loci and observed evidence for genetic regulation of DNA methylation in SLE.  

    In conclusion, the results presented in this thesis provide new insights into the molecular mechanisms underlying autoimmunity in pSS and SLE. The studies confirm the central role of the interferon system in pSS and SLE and further suggest novel genes and mechanisms to be involved in the pathogenesis these autoimmune diseases.

    List of papers
    1. Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes
    Open this publication in new window or tab >>Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes
    Show others...
    2016 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 11, p. 2029-2036Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.

    METHODS: Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.

    RESULTS: We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.

    CONCLUSIONS: Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:uu:diva-278026 (URN)10.1136/annrheumdis-2015-208659 (DOI)000386469300023 ()26857698 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationSwedish Society for Medical Research (SSMF), 521-2014-2263 521-2013-2830Swedish Research Council, 350-2012-256Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Note

    De 2 första författarna delar förstaförfattarskapet.

    Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2022-01-29Bibliographically approved
    2. Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome
    Open this publication in new window or tab >>Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome
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    2016 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 55, no 6, p. 1074-1082Article in journal (Refereed) Published
    Abstract [en]

    Objective. Chronic fatigue is a common, disabling and poorly understood phenomenon. Recent studies indicate that epigenetic mechanisms may be involved in the expression of fatigue, a prominent feature of primary SS (pSS). The aim of this study was to investigate whether DNA methylation profiles of whole blood are associated with fatigue in patients with pSS. Methods. Forty-eight pSS patients with high (n = 24) or low (n = 24) fatigue as measured by a visual analogue scale were included. Genome-wide DNA methylation was investigated using the Illumina HumanMethylation450 BeadChip array. After quality control, a total of 383 358 Cytosine-phosphate-Guanine (CpG) sites remained for further analysis. Age, sex and differential cell count estimates were included as covariates in the association model. A false discovery rate-corrected P < 0.05 was considered significant, and a cut-off of 3% average difference in methylation levels between high- and low-fatigue patients was applied. Results. A total of 251 differentially methylated CpG sites were associated with fatigue. The CpG site with the most pronounced hypomethylation in pSS high fatigue annotated to the SBF2-antisense RNA1 gene. The most distinct hypermethylation was observed at a CpG site annotated to the lymphotoxin alpha gene. Functional pathway analysis of genes with differently methylated CpG sites in subjects with high vs low fatigue revealed enrichment in several pathways associated with innate and adaptive immunity. Conclusion. Some genes involved in regulation of the immune system and in inflammation are differently methylated in pSS patients with high vs low fatigue. These findings point to functional networks that may underlie fatigue. Epigenetic changes could constitute a fatigue-regulating mechanism in pSS.

    Keywords
    primary Sjogren's syndrome, epigenetics, DNA methylation, fatigue
    National Category
    Rheumatology and Autoimmunity
    Identifiers
    urn:nbn:se:uu:diva-299502 (URN)10.1093/rheumatology/kew008 (DOI)000377432200015 ()
    Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2017-11-28Bibliographically approved
    3. Transcription profiling in CD19+ B-cells in primary Sjögren's syndrome reveals an interferon-signature with upregulated BAFF and TLR7
    Open this publication in new window or tab >>Transcription profiling in CD19+ B-cells in primary Sjögren's syndrome reveals an interferon-signature with upregulated BAFF and TLR7
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-310386 (URN)
    Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2016-12-14
    4. DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus (SLE)
    Open this publication in new window or tab >>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus (SLE)
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-310387 (URN)
    Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2016-12-14
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  • 114.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Bengtsson, Anders A
    Lund University, Skane University Hospital, Lund, Sweden.
    Jönsen, Andreas
    Lund University, Skane University Hospital, Lund, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Stockholm, Sweden.
    Sjöwall, Christopher
    Linköping University, Linköping, Sweden.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

    Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

    Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

    Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

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  • 115.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Padyukov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Rheumatol AIR, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 2654Article in journal (Other academic)
  • 116.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Carlsson Almlöf, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöwall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Rheumatol, Linkoping, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sect Rheumatol, Uppsala, Sweden;Uppsala Univ, Sci Life Lab, Dept Med Sci, Uppsala, Sweden.
    Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogren's Syndrome2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed)
    Abstract [en]

    Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogren's syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.

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  • 117.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rantapaa-Dahlqvist, S.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Bengtsson, A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden.
    Jonsen, A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden.
    Padyukov, L.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Svenungsson, E.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Sjowall, C.
    Linkoping Univ, Rheumatol Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 3-3Article in journal (Other academic)
  • 118.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Signer, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norheim, Katrine B.
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Eloranta, Majia-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvanen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hypomethylation in Enhancer and Promoter Regions of Interferon Regulated Genes in Multiple Tissues Is Associated with Primary Sjogren's Syndrome2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no Suppl. 10, article id 2100Article in journal (Other academic)
  • 119.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Signér, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norheim, Katrine Braekke
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway.
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes2016In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, no 11, p. 2029-2036Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.

    METHODS: Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.

    RESULTS: We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.

    CONCLUSIONS: Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

    Download full text (pdf)
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  • 120.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bjork, A.
    Karolinska Inst, Dept Med, Karolinska Univ Hosp, Stockholm, Sweden.
    Nordlund, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kvarnstrom, M.
    Karolinska Inst, Dept Med, Karolinska Univ Hosp, Stockholm, Sweden.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wahren-Herlenius, M.
    Karolinska Inst, Dept Med, Karolinska Univ Hosp, Stockholm, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature2018In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 87, no 5, article id UNSP e12662Article in journal (Refereed)
    Abstract [en]

    B cells play a key role in the pathogenesis of primary Sjogren's syndrome (pSS). The aim of this study was to analyse the transcriptome of CD19+ B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. RNA from purified CD19+ B cells from 12 anti-SSA antibody-positive untreated female patients with pSS and 20 healthy blood donors was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of <0.05 was applied to define differential gene expression. As validation, gene expression in B cells from 17 patients with pSS and 16 healthy controls was analysed using a targeted gene panel. RNA-sequencing identified 4047 differentially expressed autosomal genes in pSS B cells. Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. Among the top upregulated and validated genes were CX3CR1, encoding the fractalkine receptor involved in regulation of B-cell malignancies, CCL5/RANTES and CCR1. Increased expression of several members of the TNF superfamily was also identified; TNFSF4/Ox40L, TNFSF10/TRAIL, TNFSF13B/BAFF, TNFRSF17/BCMA as well as S100A8 and -A9/calprotectin, TLR7, STAT1 and STAT2. Among genes with downregulated expression in pSS B cells were SOCS1 and SOCS3, CD70 and TNFAIP3/A20. We conclude that B cells from patients with anti-SSA antibody-positive pSS display immune activation with upregulated expression of chemokines, chemokine receptors and a prominent type I and type II IFN signature, while suppressors of cytokine signalling are downregulated. This adds insight into the autoimmune process and suggests potential targets for future functional studies.

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  • 121.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Omdal, Roald
    Norheim, Katrine Braekke
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-Wide Analysis of DNA Methylation Profiles in Multiple Tissues in Primary Sjogren's Syndrome2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 412-412Article in journal (Other academic)
  • 122.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Sandling, Johanna K.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Norheim, Katrine Braekke
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Johnsen, Svein Joar Auglaend
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA Methylation-Based Interferon Scores Associate With Sub-Phenotypes in Primary Sjögren's Syndrome2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 702037Article in journal (Refereed)
    Abstract [en]

    Primary Sjogren's syndrome (pSS) is an autoimmune inflammatory disease with profound clinical heterogeneity, where excessive activation of the type I interferon (IFN) system is considered one of the key mechanisms in disease pathogenesis. Here we present a DNA methylation-based IFN system activation score (DNAm IFN score) and investigate its potential associations with sub-phenotypes of pSS. The study comprised 100 Swedish patients with pSS and 587 Swedish controls. For replication, 48 patients with pSS from Stavanger, Norway, were included. IFN scores were calculated from DNA methylation levels at the IFN-induced genes RSAD2, IFIT1 and IFI44L. A high DNAm IFN score, defined as > mean(controls) +2SD(controls) (IFN score > 4.4), was observed in 59% of pSS patients and in 4% of controls (p=1.3x10(-35)). Patients with a high DNAm IFN score were on average seven years younger at symptom onset (p=0.017) and at diagnosis (p=3x10(-3)). The DNAm IFN score levels were significantly higher in pSS positive for both SSA and SSB antibodies compared to SSA/SSB negative patients (p(discovery)=1.9x10(-8), p(replication)=7.8x10(-4)). In patients positive for both SSA subtypes Ro52 and Ro60, an increased score was identified compared to single positive patients (p=0.022). Analyzing the discovery and replication cohorts together, elevated DNAm IFN scores were observed in pSS with hypergammaglobulinemia (p=2x10(-8)) and low C4 (p=1.5x10(-3)) compared to patients without these manifestations. Patients < 70 years with ongoing lymphoma at DNA sampling or lymphoma at follow-up (n=7), presented an increased DNAm IFN score compared to pSS without lymphoma (p=0.025). In conclusion, the DNAm-based IFN score is a promising alternative to mRNA-based scores for identification of patients with activation of the IFN system and may be applied for patient stratification guiding treatment decisions, monitoring and inclusion in clinical trials.

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  • 123.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Langenberg, Claudia
    Hivert, Marie-France
    Prokopenko, Inga
    Lyssenko, Valeriya
    Dupuis, Josée
    Mägi, Reedik
    Sharp, Stephen
    Jackson, Anne U.
    Assimes, Themistocles L.
    Shrader, Peter
    Knowles, Joshua W.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Abbasi, Fahim A.
    Bergman, Richard N.
    Bergmann, Antje
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boehnke, Michael
    Bonnycastle, Lori L.
    Bornstein, Stefan R.
    Buchanan, Thomas A.
    Bumpstead, Suzannah J.
    Böttcher, Yvonne
    Chines, Peter
    Collins, Francis S.
    Cooper, Cyrus C.
    Dennison, Elaine M.
    Erdos, Michael R.
    Ferrannini, Ele
    Fox, Caroline S.
    Graessler, Jürgen
    Hao, Ke
    Isomaa, Bo
    Jameson, Karen A.
    Kovacs, Peter
    Kuusisto, Johanna
    Laakso, Markku
    Ladenvall, Claes
    Mohlke, Karen L.
    Morken, Mario A.
    Narisu, Narisu
    Nathan, David M.
    Pascoe, Laura
    Payne, Felicity
    Petrie, John R.
    Sayer, Avan A.
    Schwarz, Peter E. H.
    Scott, Laura J.
    Stringham, Heather M.
    Stumvoll, Michael
    Swift, Amy J.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Tönjes, Anke
    Valle, Timo T.
    Williams, Gordon H.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barroso, Inês
    Quertermous, Thomas
    Walker, Mark
    Wareham, Nicholas J.
    Meigs, James B.
    McCarthy, Mark I.
    Groop, Leif
    Watanabe, Richard M.
    Florez, Jose C.
    Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans2010In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, no 5, p. 1266-1275Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.

    RESEARCH DESIGN AND METHODS

    We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).

    RESULTS

    The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.

    CONCLUSIONS

    Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

  • 124.
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans.

    Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell.

    Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses.

    The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties.

    In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming.

    These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.

    List of papers
    1. Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
    Open this publication in new window or tab >>Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
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    2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 11, p. e3682-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: We have previously shown that vaccination with DNA encoding the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)(91-108) (pMOG) suppresses MOG(91-108)-induced rat Experimental Autoimmune Encephalomyelitis (EAE), a model for human Multiple Sclerosis (MS). The suppressive effect of pMOG is dependent on inclusion of CpG DNA in the plasmid backbone and is associated with early induction of Interferon (IFN)-beta. PRINCIPAL FINDINGS: In this study we examined the mechanisms underlying pMOG-induced protection. We found that in the DNA vaccinated cohort proinflammatory Interleukin (IL)-17 and IL-21 responses were dramatically reduced compared to in the control group, but that the expression of Foxp3 and Tumor Growth Factor (TGF)-beta1, which are associated with regulatory T cells, was not enhanced. Moreover, genes associated with Type I IFNs were upregulated. To delineate the role of IFN-beta in the protective mechanism we employed short interfering RNA (siRNA) to IFN-beta in the DNA vaccine. SiRNA to IFN-beta completely abrogated the protective effects of the vaccine, demonstrating that a local early elaboration of IFN-beta is important for EAE protection. IL-17 responses comparable to those in control rats developed in rats injected with the IFN-beta-silencing DNA vaccine. CONCLUSIONS: We herein demonstrate that DNA vaccination protects from proinflammatory Th17 cell responses during induction of EAE. The mechanism involves IFN-beta as IL-17 responses are rescued by silencing of IFN-beta during DNA vaccination.

    Place, publisher, year, edition, pages
    PLoS, 2008
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102743 (URN)10.1371/journal.pone.0003682 (DOI)000265165500005 ()18997868 (PubMedID)1932-6203 (Electronic) (ISBN)
    Available from: 2009-05-12 Created: 2009-05-11 Last updated: 2020-11-04Bibliographically approved
    2. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis
    Open this publication in new window or tab >>Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis
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    2008 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 38, no 2, p. 565-575Article in journal (Refereed) Published
    Abstract [en]

    Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88(-/-) mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88(-/-) mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4(-/-) and TLR9(-/-) mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4(-/-) mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9(-/-) mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOG-induced EAE.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13139 (URN)10.1002/eji.200737187 (DOI)000253326100025 ()18203139 (PubMedID)
    Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2022-01-28Bibliographically approved
    3. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
    Open this publication in new window or tab >>Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
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    2009 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 39, no 10, p. 2925-2935Article in journal (Refereed) Published
    Abstract [en]

    EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17- and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-alpha/beta secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE. In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.

    Keywords
    Autoimmunity, DC, EAE/MS, T cells, Type I IFN
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-108362 (URN)10.1002/eji.200839179 (DOI)000271151000030 ()19637225 (PubMedID)
    Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2022-01-28Bibliographically approved
    4. Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE
    Open this publication in new window or tab >>Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE
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    2012 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 42, no 10, p. 2555-2563Article in journal (Refereed) Published
    Abstract [en]

    EAE, an animal model for multiple sclerosis, is a Th17- and Th1-cell-mediated auto-immune disease, but the mechanisms leading to priming of encephalitogenicTcells in autoimmune neuroinflammation are poorly understood. To investigate the role of dendritic cells (DCs) in the initiation of autoimmuneTh17- andTh1-cell responses andEAE, we used mice transgenic for a simian diphtheria toxin receptor (DTR) expressed under the control of the murineCD11c promoter (CD11c-DTRmice onC57BL/6 background).EAEwas induced by immunization with myelin oligodendrocyte glycoprotein (MOG) protein in CFA. DCs were depleted on the day before and 8 days afterMOG immunization. The mean clinicalEAEscore was only mildly reduced inDC-depleted mice when DCs were ablated beforeEAEinduction. The frequency of activatedTh cells was not altered, andMOG-inducedTh17 orTh1-cell responses were not altered, in the spleens ofDC-depleted mice. Similar results were obtained ifDCswere ablated the first 10 days afterMOGimmunization with repeatedDCdepletions. Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-inducedTh17 andTh1-cell responses or the incidence ofEAE. Thus, the mechansim of priming ofTh cells inEAEremains to be elucidated.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-173266 (URN)10.1002/eji.201142239 (DOI)000309610200004 ()22806332 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2012-04-23 Created: 2012-04-21 Last updated: 2020-11-04Bibliographically approved
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  • 125.
    Iurilli, Maria L. C.
    et al.
    Imperial Coll London, London, England.
    Yi-Ting, Lin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Filippi, Sarah
    Imperial Coll London, London, England.
    Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e60060Article in journal (Refereed)
    Abstract [en]

    From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.

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  • 126. Ivanov Öfverholm, I.
    et al.
    Zachariadis, V.
    Taylan, F.
    Marincevic-Zuniga, Yanara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tran, A. N.
    Saft, L.
    Nilsson, D.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönnerholm, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Harila-Saari, A.
    Nordenskjöld, M.
    Heyman, M.
    Nordgren, A.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Barbany, G.
    Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia2020In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 61, no 3, p. 604-613Article in journal (Refereed)
    Abstract [en]

    Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.

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  • 127.
    Jacobsson, Josefin A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The common FTO variant rs9939609 is not associated with BMI in a longitudinal study on a cohort of Swedish men born 1920-19242009In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 10, no 131, p. 131-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Common FTO (fat mass and obesity associated) gene variants have recently been strongly associated with body mass index and obesity in several large studies. Here we set out to examine the association of the FTO variant rs9939609 with BMI in a 32 year follow up study of men born 1920-1924. Moreover, we analyzed the effect of physical activity on the different genotypes. METHODS: The FTO rs9936609 was genotyped using an Illumina golden gate assay. BMI was calculated using standard methods and body fat was estimated by measuring skinfold thickness using a Harpenden caliper. Physical activity was assessed using a four question medical questionnaire. RESULTS: FTO rs9939609 was genotyped in 1153 elderly Swedish men taking part of a population-based cohort study, the ULSAM cohort. The risk of obesity and differences in BMI according to genotype at the ages of 50, 60, 70, 77 and 82 were investigated. We found no increased risk of obesity and no association with BMI at any age with the FTO rs9939609 variant. We found however interaction between physical activity at the age of 50 years and genotype on BMI levels (p = 0.039) and there was a clear trend towards larger BMI differences between the TT and AA carriers as well as between AT and AA carriers in the less physically active subjects. CONCLUSION: Here we found that the well established obesity risk allele for a common variant in FTO does not associate with increased BMI levels in a Swedish population of adult men which reached adulthood before the appearance of today's obesogenic enviroment. There is an interaction between physical activity and the effect of the FTO genotype on BMI levels suggesting that lack of physical activity is a requirement for an association of FTO gene variants to obesity.

  • 128.
    Jacobsson, Josefin A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hedberg, Lilia A.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 5, p. e20158-Article in journal (Refereed)
    Abstract [en]

    Background

     The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution.

    Objective

    To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans.

    Design

    Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort.

    Results

     Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women.

    Conclusions

    Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.

  • 129. Jiao, Hong
    et al.
    Arner, Peter
    Dickson, Suzanne L.
    Vidal, Hubert
    Mejhert, Niklas
    Henegar, Corneliu
    Taube, Magdalena
    Hansson, Caroline
    Hinney, Anke
    Galan, Pilar
    Simon, Chantal
    Silveira, Angela
    Benrick, Anna
    Jansson, John-Olov
    Bouloumie, Anne
    Langin, Dominique
    Laville, Martine
    Debard, Cyrille
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rydén, Mikael
    Kere, Juha
    Dahlman-Wright, Karin
    Hamsten, Anders
    Clement, Karine
    Dahlman, Ingrid
    Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 6, p. E962-E966Article in journal (Refereed)
    Abstract [en]

    Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.

  • 130. Jiao, Hong
    et al.
    Arner, Peter
    Hoffstedt, Johan
    Brodin, David
    Dubern, Beatrice
    Czernichow, Sebastien
    van't Hooft, Ferdinand
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pedersen, Oluf
    Hansen, Torben
    Sorensen, Thorkild I. A.
    Hebebrand, Johannes
    Kere, Juha
    Dahlman-Wright, Karin
    Hamsten, Anders
    Clement, Karine
    Dahlman, Ingrid
    Genome wide association study identifies KCNMA1 contributing to human obesity2011In: BMC Medical Genomics, E-ISSN 1755-8794, Vol. 4, p. 51-Article in journal (Refereed)
    Abstract [en]

    Background: Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity. Methods: We performed a GWA analysis in 164 morbidly obese subjects (BMI: body mass index > 40 kg/m(2)) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal P< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for 14 adults. Results: Potassium channel, calcium activated, large conductance, subfamily M, alpha member (KCNMA1) rs2116830*G and BDNF rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for KCNMA1 rs2116830*G with P = 2.82 x 10(-10) and an odds ratio (OR) based on cases vs controls of 1.26 [95% C. I. 1.12-1.41] and for BDNF rs988712*G with P = 5.2 x 10(-17) and an OR of 1.36 [95% C. I. 1.20-1.55]. KCNMA1 rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (P = 0.0001) and fat cell (P = 0.04) expression of KCNMA1 was increased in obesity. Conclusions: We have identified KCNMA1 as a new susceptibility locus for obesity, and confirmed the association of the BDNF locus at the genome-wide significant level.

  • 131.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Becker, Richard C.
    Storey, Robert F.
    Himmelmann, Anders
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Barratt, Bryan J.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Katus, Hugo A.
    Steg, Philippe Gabriel
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients With Acute Coronary Syndromes Genome-Wide Association Study in the PLATelet inhibition and patient Outcomes Trial (PLATO)2015In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 8, no 3, p. 498-506Article in journal (Refereed)
    Abstract [en]

    Background Interleukin 18 (IL-18) promotes atherosclerotic plaque formation and is increased in patients with acute coronary syndromes. However the relative contribution of genetic variants to the IL-18 levels has not been fully determined. Methods and Results Baseline plasma IL-18 levels were measured in 16633 patients with acute coronary syndrome, of whom 9340 had genetic data that passed genotype quality control. A 2-stage genome-wide association study was performed, followed by combined analyses using >10 million genotyped or imputed genetic markers. Single nucleotide polymorphisms at 3 loci (IL18, NLRC4, and MROH6) were identified (P<3.15x10(-8)) in the discovery cohort (n=3777) and replicated in the remaining patients (n=5563). In the pooled data (discovery+replication cohort), 7 independent associations, in 5 chromosomal regions, were associated with IL-18 levels (minimum P=6.99x10(-72)). Six single nucleotide polymorphisms are located in predicted promoter regions of which one disrupts a transcription factor binding site. One single nucleotide polymorphism in NLRC4 is a rare missense variant, predicted to be deleterious to the protein. Altogether, the identified genetic variants explained 8% of the total variation in IL-18 levels in the cohort. Conclusions Our results show that genetic variants play an important role in determining IL-18 levels in patients with acute coronary syndrome and we have identified genetic variants located in the IL-18 gene (IL18) or close to genes that are involved in procaspase-1 activation (NLRC4 and CARD16, CARD17, and CARD18). These associations also highlight the importance of the NLRC4 inflammasome for IL-18 production in acute coronary syndrome patients.

  • 132.
    Johansson, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindholm, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Barratt, Bryan J.
    AstraZeneca R&D, Alderley Pk SK10 4TF, Cheshire, England..
    Becker, Richard C.
    Acad Hlth Ctr, Div Cardiovasc Hlth & Dis, Heart Lung & Vasc Inst, Cincinnati, OH 45267 USA..
    Himmelmann, Anders
    AstraZeneca Res & Dev, S-43150 Molndal, Sweden..
    Katus, Hugo A.
    Univ Klinikum Heidelberg, Med Klin, D-69120 Heidelberg, Germany..
    Steg, Philippe Gabriel
    INSERM, Unite 1148, F-75019 Paris, France.;Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75018 Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France.;Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6NP, England..
    Storey, Robert F.
    Univ Sheffield, Dept Cardiovasc Sci, Sheffield S10 2RX, S Yorkshire, England..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Genome-wide association and Mendelian randomization study of NT-proBNP in patients with acute coronary syndrome2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 7, p. 1447-1456Article in journal (Refereed)
    Abstract [en]

    N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci (SLC39A8 and POC1B/GALNT4) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10(-15)) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10(-10)), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10(-16)) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08-1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8, these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: ; NCT00391872.

  • 133. Jonsson, Erik G.
    et al.
    Saetre, Peter
    Vares, Maria
    Andreou, Dimitrios
    Larsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Timm, Sally
    Rasmussen, B
    Djurovic, Srdjan
    Melle, Ingrid
    Andreassen, A
    Agartz, Ingrid
    Werge, Thomas
    Hall, Håkan
    Terenius, Lars
    DTNBP1, NRG1, DAOA, DAO and GRM3 Polymorphisms and Schizophrenia: An Association Study2009In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 59, no 3, p. 142-150Article in journal (Refereed)
    Abstract [en]

    Background: Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. Methods: In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. Results: One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. Conclusions: The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships. Copyright (C) 2009 S. Karger AG, Basel

  • 134.
    Kaleviste, Epp
    et al.
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Saare, Mario
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Leahy, Timothy Ronan
    Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland.
    Bondet, Vincent
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Duffy, Darragh
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Mogensen, Trine H.
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Jörgensen, Sofie E.
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.
    Nurm, Helke
    Tallinn Childrens Hosp, Dept Emergency Care & Acute Infect, Tallinn, Estonia.
    Ip, Winnie
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Davies, E. Graham
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Sauer, Sascha
    Max Planck Inst Mol Genet, Otto Warburg Lab, Berlin, Germany;Max Delbruck Ctr Mol Med, BIMSB, BIH, Lab Funct Genom Nutrigen & Syst Biol, Berlin, Germany.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Kisand, Kai
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined2019In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 49, no 5, p. 790-800Article in journal (Refereed)
    Abstract [en]

    STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-alpha were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-alpha levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

  • 135. Kanoni, Stavroula
    et al.
    Nettleton, Jennifer A.
    Hivert, Marie-France
    Ye, Zheng
    van Rooij, Frank J. A.
    Shungin, Dmitry
    Sonestedt, Emily
    Ngwa, Julius S.
    Wojczynski, Mary K.
    Lemaitre, Rozenn N.
    Gustafsson, Stefan
    Anderson, Jennifer S.
    Tanaka, Toshiko
    Hindy, George
    Saylor, Georgia
    Renstrom, Frida
    Bennett, Amanda J.
    van Duijn, Cornelia M.
    Florez, Jose C.
    Fox, Caroline S.
    Hofman, Albert
    Hoogeveen, Ron C.
    Houston, Denise K.
    Hu, Frank B.
    Jacques, Paul F.
    Johansson, Ingegerd
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Liu, Yongmei
    McKeown, Nicola
    Ordovas, Jose
    Pankow, James S.
    Sijbrands, Eric J. G.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Uitterlinden, Andre G.
    Yannakoulia, Mary
    Zillikens, M. Carola
    Wareham, Nick J.
    Prokopenko, Inga
    Bandinelli, Stefania
    Forouhi, Nita G.
    Cupples, L. Adrienne
    Loos, Ruth J.
    Hallmans, Goran
    Dupuis, Josee
    Langenberg, Claudia
    Ferrucci, Luigi
    Kritchevsky, Stephen B.
    McCarthy, Mark I.
    Ingelsson, Erik
    Borecki, Ingrid B.
    Witteman, Jacqueline C. M.
    Orho-Melander, Marju
    Siscovick, David S.
    Meigs, James B.
    Franks, Paul W.
    Dedoussis, George V.
    Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 9, p. 2407-2416Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for beta-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

    RESEARCH DESIGN AND METHODS

    We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

    RESULTS

    We observed a significant association of total zinc intake with lower fasting glucose levels (beta-coefficient +/- SE per 1 mg/day of zinc intake: -0.0012 +/- 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (beta-coefficient +/- SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 +/- 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

    CONCLUSIONS

    Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

  • 136. Karlsson, Robert
    et al.
    Graae, Lisette
    Lekman, Magnus
    Wang, Dai
    Favis, Reyna
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Galter, Dagmar
    Belin, Andrea Carmine
    Paddock, Silvia
    MAGI1 Copy Number Variation in Bipolar Affective Disorder and Schizophrenia2012In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 71, no 10, p. 922-930Article in journal (Refereed)
    Abstract [en]

    Background: Bipolar affective disorder (BPAD) and schizophrenia (SZ) are devastating psychiatric disorders that each affect about 1% of the population worldwide. Identification of new drug targets is an important step toward better treatment of these poorly understood diseases.

    Methods: Genome-wide copy number variation (CNV) was assessed and variants were ranked by co-occurrence with disease in 48 BPAD families. Additional support for involvement of the highest-ranking CNV from the family-based analysis in psychiatric disease was obtained through analysis of 4084 samples with BPAD, SZ, or schizoaffective disorder. Finally, a pooled analysis of in-house and published datasets was carried out including 10,925 cases with BPAD, SZ, or schizoaffective disorder and 16,747 controls.

    Results: In the family-based analysis, an approximately 200 kilobase (kb) deletion in the first intron of the MAGI1 gene was identified that segregated with BPAD in a pedigree (six out of six affected individuals; parametric logarithm of the odds score = 1.14). In the pooled analysis, seven additional insertions or deletions over 100 kb were identified in MAGI1 in cases, while only two such CNV events were identified in the same gene in controls (p = .023; Fisher's exact test). Because earlier work had identified a CNV in the close relative MAGI2 in SZ, the study was extended to include MAGI2. In the pooled analysis of MAGI2, two large deletions were found in cases, and two duplications were detected in controls.

    Conclusions: Results presented herein provide further evidence for a role of MAGI1 and MAGI2 in BPAD and SZ etiology.

  • 137.
    Kiialainen, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ahlford, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Performance of Microarray and Liquid Based Capture Methods for Target Enrichment for Massively Parallel Sequencing and SNP Discovery2011In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 2, p. e16486-Article in journal (Refereed)
    Abstract [en]

    Targeted sequencing is a cost-efficient way to obtain answers to biological questions in many projects, but the choice of the enrichment method to use can be difficult. In this study we compared two hybridization methods for target enrichment for massively parallel sequencing and single nucleotide polymorphism (SNP) discovery, namely Nimblegen sequence capture arrays and the SureSelect liquid-based hybrid capture system. We prepared sequencing libraries from three HapMap samples using both methods, sequenced the libraries on the Illumina Genome Analyzer, mapped the sequencing reads back to the genome, and called variants in the sequences. 74-75% of the sequence reads originated from the targeted region in the SureSelect libraries and 41-67% in the Nimblegen libraries. We could sequence up to 99.9% and 99.5% of the regions targeted by capture probes from the SureSelect libraries and from the Nimblegen libraries, respectively. The Nimblegen probes covered 0.6 Mb more of the original 3.1 Mb target region than the SureSelect probes. In each sample, we called more SNPs and detected more novel SNPs from the libraries that were prepared using the Nimblegen method. Thus the Nimblegen method gave better results when judged by the number of SNPs called, but this came at the cost of more over-sampling.

  • 138. Kilarski, Laura L.
    et al.
    Achterberg, Sefanja
    Devan, William J.
    Traylor, Matthew
    Malik, Rainer
    Lindgren, Arne
    Pare, Guillame
    Sharma, Pankaj
    Slowik, Agniesczka
    Thijs, Vincent
    Walters, Matthew
    Worrall, Bradford B.
    Sale, Michele M.
    Algra, Ale
    Kappelle, L. Jaap
    Wijmenga, Cisca
    Norrving, Bo
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Goris, An
    Franke, Andre
    Sudlow, Cathie
    Rothwell, Peter M.
    Levi, Christopher
    Holliday, Elizabeth G.
    Fornage, Myriam
    Psaty, Bruce
    Gretarsdottir, Solveig
    Thorsteinsdottir, Unnar
    Seshadri, Sudha
    Mitchell, Braxton D.
    Kittner, Steven
    Clarke, Robert
    Hopewell, Jemma C.
    Bis, Joshua C.
    Boncoraglio, Giorgio B.
    Meschia, James
    Ikram, M. Arfan
    Hansen, Bjorn M.
    Montaner, Joan
    Thorleifsson, Gudmar
    Stefanson, Kari
    Rosand, Jonathan
    de Bakker, Paul I. W.
    Farrall, Martin
    Dichgans, Martin
    Markus, Hugh S.
    Bevan, Steve
    Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.122014In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 83, no 8, p. 678-685Article in journal (Refereed)
    Abstract [en]

    Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 x 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695). Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

  • 139. Kilpelainen, Tuomas O.
    et al.
    Zillikens, M. Carola
    Stancakova, Alena
    Finucane, Francis M.
    Ried, Janina S.
    Langenberg, Claudia
    Zhang, Weihua
    Beckmann, Jacques S.
    Luan, Jian'an
    Vandenput, Liesbeth
    Styrkarsdottir, Unnur
    Zhou, Yanhua
    Smith, Albert Vernon
    Zhao, Jing-Hua
    Amin, Najaf
    Vedantam, Sailaja
    Shin, So-Youn
    Haritunians, Talin
    Fu, Mao
    Feitosa, Mary F.
    Kumari, Meena
    Halldorsson, Bjarni V.
    Tikkanen, Emmi
    Mangino, Massimo
    Hayward, Caroline
    Song, Ci
    Arnold, Alice M.
    Aulchenko, Yurii S.
    Oostra, Ben A.
    Campbell, Harry
    Cupples, L. Adrienne
    Davis, Kathryn E.
    Doering, Angela
    Eiriksdottir, Gudny
    Estrada, Karol
    Manuel Fernandez-Real, Jose
    Garcia, Melissa
    Gieger, Christian
    Glazer, Nicole L.
    Guiducci, Candace
    Hofman, Albert
    Humphries, Steve E.
    Isomaa, Bo
    Jacobs, Leonie C.
    Jula, Antti
    Karasik, David
    Karlsson, Magnus K.
    Khaw, Kay-Tee
    Kim, Lauren J.
    Kivimaeki, Mika
    Klopp, Norman
    Kuehnel, Brigitte
    Kuusisto, Johanna
    Liu, Yongmei
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lorentzon, Mattias
    Luben, Robert N.
    McKnight, Barbara
    Mellstrom, Dan
    Mitchell, Braxton D.
    Mooser, Vincent
    Maria Moreno, Jose
    Mannisto, Satu
    O'Connell, Jeffery R.
    Pascoe, Laura
    Peltonen, Leena
    Peral, Belen
    Perola, Markus
    Psaty, Bruce M.
    Salomaa, Veikko
    Savage, David B.
    Semple, Robert K.
    Skaric-Juric, Tatjana
    Sigurdsson, Gunnar
    Song, Kijoung S.
    Spector, Timothy D.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Talmud, Philippa J.
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Uitterlinden, Andre G.
    van Duijn, Cornelia M.
    Vidal-Puig, Antonio
    Wild, Sarah H.
    Wright, Alan F.
    Clegg, Deborah J.
    Schadt, Eric
    Wilson, James F.
    Rudan, Igor
    Ripatti, Samuli
    Borecki, Ingrid B.
    Shuldiner, Alan R.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Jansson, John-Olov
    Kaplan, Robert C.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Groop, Leif
    Kiel, Douglas P.
    Rivadeneira, Fernando
    Walker, Mark
    Barroso, Ines
    Vollenweider, Peter
    Waeber, Gerard
    Chambers, John C.
    Kooner, Jaspal S.
    Soranzo, Nicole
    Hirschhorn, Joel N.
    Stefansson, Kari
    Wichmann, H-Erich
    Ohlsson, Claes
    O'Rahilly, Stephen
    Wareham, Nicholas J.
    Speliotes, Elizabeth K.
    Fox, Caroline S.
    Laakso, Markku
    Loos, Ruth J. F.
    Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 8, p. 753-U58Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

  • 140. Kjellström, A.
    et al.
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lembring, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Ahlgren, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    An Analysis of the Alleged Skeletal Remains of Carin Göring2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 12, p. e44366-Article in journal (Refereed)
    Abstract [en]

    In 1991, treasure hunters found skeletal remains in an area close to the destroyed country residence of former Nazi leader Hermann Göring in northeastern Berlin. The remains, which were believed to belong to Carin Göring, who was buried at the site, were examined to determine whether it was possible to make a positive identification. The anthropological analysis showed that the remains come from an adult woman. The DNA analysis of several bone elements showed female sex, and a reference sample from Carin's son revealed mtDNA sequences identical to the remains. The profile has one nucleotide difference from the Cambridge reference sequence (rCRS), the common variant 263G. A database search resulted in a frequency of this mtDNA sequence of about 10% out of more than 7,000 European haplotypes. The mtDNA sequence found in the ulna, the cranium and the reference sample is, thus, very common among Europeans. Therefore, nuclear DNA analysis was attempted. The remains as well as a sample from Carin's son were successfully analysed for the three nuclear markers TH01, D7S820 and D8S1179. The nuclear DNA analysis of the two samples revealed one shared allele for each of the three markers, supporting a mother and son relationship. This genetic information together with anthropological and historical files provides an additional piece of circumstantial evidence in our efforts to identify the remains of Carin Göring.

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  • 141.
    Krali, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Palle, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology. Uppsala Univ, Dept Med Sci, Mol Precis Med & Sci Life Lab, S-75237 Uppsala, Sweden.;Uppsala Univ, Dept Womens & Childrens Hlth, S-75237 Uppsala, Sweden..
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, S-41685 Gothenburg, Sweden..
    Noren-Nystrom, Ulrika
    Umeå Univ Hosp, Dept Clin Sci, Pediat, S-90185 Umeå, Sweden..
    Hasle, Henrik
    Aarhus Univ Hosp, Dept Pediat, DK-8200 Aarhus, Denmark..
    Jahnukainen, Kirsi
    Helsinki Univ Cent Hosp, Childrens Hosp, Helsinki 00290, Finland.;Univ Helsinki, Helsinki 00290, Finland..
    Jonsson, Olafur Gisli
    Landspitali Univ Hosp, Dept Pediat, IS-101 Reykjavik, Iceland..
    Hovland, Randi
    Haukeland Hosp, Ctr Med Genet & Mol Med, N-5009 Bergen, Norway..
    Lausen, Birgitte
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, DK-2100 Copenhagen, Denmark..
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Palmqvist, Lars
    Univ Gothenburg, Dept Clin Chem & Transfus Med, S-41346 Gothenburg, Sweden..
    Staffas, Anna
    Univ Gothenburg, Dept Clin Chem & Transfus Med, S-41346 Gothenburg, Sweden..
    Zeller, Bernward
    Oslo Univ Hosp, Div Paediat & Adolescent Med, N-0450 Oslo, Norway..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA Methylation Signatures Predict Cytogenetic Subtype and Outcome in Pediatric Acute Myeloid Leukemia (AML)2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 6, article id 895Article in journal (Refereed)
    Abstract [en]

    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML.

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  • 142. Kristensen, Vessela N
    et al.
    Edvardsen, Hege
    Tsalenko, Anya
    Nordgard, Silje H
    Sörlie, Therese
    Sharan, Roded
    Vailaya, Aditya
    Ben-Dor, Amir
    Lønning, Per Eystein
    Lien, Sigbjørn
    Omholt, Stig
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Yakhini, Zohar
    Børresen-Dale, Anne-Lise
    Genetic variation in putative regulatory loci controlling gene expression in breast cancer2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 20, p. 7735-7740Article in journal (Other academic)
    Abstract [en]

    Candidate single-nucleotide polymorphisms (SNPs) were analyzed for associations to an unselected whole genome pool of tumor mRNA transcripts in 50 unrelated patients with breast cancer. SNPs were selected from 203 candidate genes of the reactive oxygen species pathway. We describe a general statistical framework for the simultaneous analysis of gene expression data and SNP genotype data measured for the same cohort, which revealed significant associations between subsets of SNPs and transcripts, shedding light on the underlying biology. We identified SNPs in EGF, IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts, indicating the presence of regulatory SNPs in these genes. SNPs were found to act in trans in a total of 115 genes. SNPs in 43 of these 115 genes were found to act both in cis and in trans. Finally, subsets of SNPs that share significantly many common associations with a set of transcripts (biclusters) were identified. The subsets of transcripts that are significantly associated with the same set of SNPs or to a single SNP were shown to be functionally coherent in Gene Ontology and pathway analyses and coexpressed in other independent data sets, suggesting that many of the observed associations are within the same functional pathways. To our knowledge, this article is the first study to correlate SNP genotype data in the germ line with somatic gene expression data in breast tumors. It provides the statistical framework for further genotype expression correlation studies in cancer data sets.

  • 143.
    Kristjansdottir, Gudlaug Thora
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic Variation and Expression of the IRF5 Gene in Autoimmune Diseases2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The interferon regulatory factor 5 (IRF5) gene encodes a transcription factor that plays an important role in the innate as well as in the cell-mediated immune response. The IRF5 gene has received considerable attention since it was shown to be associated with two autoimmune diseases; systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The aim of this thesis was to examine if IRF5 is associated with other autoimmune diseases and to investigate the role of the genetic variation of IRF5. In the first study a set of common polymorphisms in IRF5 were analyzed for their association with two subgroup of inflammatory bowel disease (IBD); Crohn´s diseases (CD) and ulcerative colitis (UC). A strong signal of association of IRF5 with IBD was found. The most strongly associated polymorphism is a 5 base pair (bp) insertion-deletion (indel) in the promoter region of the IRF5 gene. The association was detected within both UC and CD, and appeared to be stronger in UC. In the second study we investigated the association of IRF5 with multiple sclerosis (MS). A similar set of polymorphisms as in the IBD study were genotyped in a cohort of MS patients and controls. The same polymorphisms that were associated with IBD were also found to be associated with MS. In the third study, we performed a comprehensive investigation of the IRF5 gene to detect most of the polymorphisms in the gene, and to determine to what extent they account for the association signals obtained from the gene. IRF5 was sequenced and 34 new polymorphisms were identified. Twenty seven of these, and 20 previously known SNPs in IRF5 were genotyped in an SLE case-control cohort. We found that only two polymorphisms, the 5bp indel and a SNP downstream of IRF5, account for the association signal from all the remaining markers in the IRF5 gene, and that these two polymorphisms are independently associated with SLE. Interestingly, in our studies on IBD and MS, we only observed the signal from the 5bp indel polymorphism as a risk factor for IBDs. In the fourth study the two independent risk alleles in IRF5, were tested for their association with primary Sjögren´s syndrome (pSS). In this study we also included one SNP in the STAT4 gene, since STAT4 had recently been shown to be associated with SLE. Both risk factors in IRF5 and STAT4 were found to be associated with pSS.

    The regulation of expression of IRF5 was also investigated in the first three studies. We observed allele-specific differences in protein binding as well as increased binding of the transcription factor SP1 to the 5bp risk allele. We also detected increased expression of the IRF5 mRNA from a promoter containing the risk allele.

    Taken together, the results of our studies suggest a general function for IRF5 as a regulator of the autoimmune response, where the 5bp indel is associated with IBD, MS, SLE and pSS. The additionally polymorphisms, which account for the remaining association signal obtained with SLE and pSS, may contribute to the disease manifestations that are specific for rheumatic diseases. Our studies add to the evidence that there are genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

    List of papers
    1. An insertion-deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases
    Open this publication in new window or tab >>An insertion-deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases
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    2007 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, no 24, p. 3008-3016Article in journal (Refereed) Published
    Abstract [en]

    The interferon regulatory factor 5 (IRF5) gene encodes a transcriptionfactor that plays an important role in the innate as well asin the cell-mediated immune responses. The IRF5 gene has beenshown to be associated with systemic lupus erythematosus andrheumatoid arthritis. We studied whether the IRF5 gene is alsoassociated with inflammatory bowel diseases (IBD), Crohn disease(CD) and ulcerative colitis (UC). Twelve polymorphisms in theIRF5 gene were genotyped in a cohort of 1007 IBD patients (748CD and 241 UC) and 241 controls from Wallonia, Belgium. Thesame polymorphisms were genotyped in a confirmatory cohort of311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven,Belgium. A strong signal of association (p = 1.9 x 10–5,OR: 1.81 (1.37-2.39)) with IBD was observed for a 5bp indel(CGGGG) polymorphism in the promoter region of the IRF5 gene.The association was detectable (p = 6.8 x 10–4) also inCD patients, and was particularly strong among the UC patients(p = 5.3 x 10–8, OR 2.42 (1.76 -3.34)). The associationof the CGGGG indel was confirmed in the second cohort (p = 3.2x 10–5, OR 1.59 (1.28 - 1.98)). The insertion of one CGGGGunit is predicted to create an additional binding site for thetranscription factor SP1. Using an electrophoretic mobilityshift assay we show allele-specific differences in protein bindingto this repetitive DNA-stretch, which suggest a potential functionrole for the CGGGG indel.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-12816 (URN)10.1093/hmg/ddm259 (DOI)000251036500003 ()17881657 (PubMedID)
    Available from: 2008-01-16 Created: 2008-01-16 Last updated: 2022-01-28Bibliographically approved
    2. Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
    Open this publication in new window or tab >>Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
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    2008 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 45, no 6, p. 362-369Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). METHODS: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. RESULTS: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p<0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel. CONCLUSION: These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-16560 (URN)10.1136/jmg.2007.055012 (DOI)000256369500006 ()18285424 (PubMedID)
    Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2022-09-15
    3. Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
    Open this publication in new window or tab >>Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
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    2008 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, no 6, p. 872-881Article in journal (Refereed) Published
    Abstract [en]

    We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-16567 (URN)10.1093/hmg/ddm359 (DOI)000253832700011 ()18063667 (PubMedID)
    Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2022-01-28Bibliographically approved
    4. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogrens syndrome
    Open this publication in new window or tab >>Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogrens syndrome
    Show others...
    2009 (English)In: GENES AND IMMUNITY, ISSN 1466-4879, Vol. 10, no 1, p. 68-76Article in journal (Refereed) Published
    Abstract [en]

    Primary Sjogrens syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) > 1.4 and P-values < 0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P = 2.5 x 10(-9). The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

    Keywords
    primary Sjogrens syndrome, IRF5, STAT4, single nucleotide polymorphisms, insertion-deletion polymorphism
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16624 (URN)10.1038/gene.2008.94 (DOI)
    Available from: 2009-02-08 Created: 2009-02-06 Last updated: 2013-10-25
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  • 144.
    Kurland, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hashemi, Nashmil
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial2008In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, no 7, p. 836-839Article in journal (Refereed)
    Abstract [en]

    Background 

    The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms.

    Methods 

    Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 ± 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing.

    Results 

    Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes.

    Conclusions 

    There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration–response relationship of an antihypertensive drug may be genotype dependent.

  • 145. Lahermo, P
    et al.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Alnaes, Grethe
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Brookes, Anthony J
    Ellonen, Pekka
    Groop, Per-Henrik
    Halldén, Christer
    Holmberg, Dan
    Holmberg, Kristina
    Keinänen, Mauri
    Kepp, Katrin
    Kere, Juha
    Kiviluoma, P
    Kristensen, Vessela
    Lindgren, Cecilia
    Odeberg, Jacob
    Osterman, Pia
    Parkkonen, Maija
    Saarela, Janna
    Sterner, Maria
    Strömqvist, Linda
    Talas, Ulvi
    Wessman, Maija
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    A quality assessment survey of SNP genotyping laboratories2006In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 27, no 7, p. 711-714Article in journal (Other academic)
    Abstract [en]

    To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.

  • 146.
    Langefeld, Carl D.
    et al.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Ainsworth, Hannah C.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Graham, Deborah S. Cunninghame
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Kelly, Jennifer A.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Comeau, Mary E.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Marion, Miranda C.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Howard, Timothy D.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Ctr Human Genom & Personalized Med Res, Winston Salem, NC 27101 USA..
    Ramos, Paula S.
    Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA.;Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Croker, Jennifer A.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Morris, David L.
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Acevedo-Vasquez, Eduardo M.
    Univ Nacl Mayor San Marcos, Fac Med, Dept Reumatol, Lima 15081, Peru..
    Alarcon, Graciela S.
    Babini, Alejandra M.
    Hosp Italiano Cordoba, Cordoba, Argentina..
    Baca, Vicente
    Hosp Pediat Mexico City, Ctr Med Nacl Siglo XXI, Inst Mexicano Seguro Social, Mexico City 06720, DF, Mexico..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, S-22362 Lund, Sweden..
    Berbotto, Guillermo A.
    Hosp Eva Peron, Granadero Baigorria, Argentina..
    Bijl, Marc
    Martini Hosp, Dept Internal Med & Rheumatol, NL-9728 NT Groningen, Netherlands..
    Brown, Elizabeth E.
    Brunner, Hermine I.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Rheumatol, Cincinnati, OH 45229 USA.;Univ Cincinnati, Cincinnati, OH 45229 USA..
    Cardiel, Mario H.
    Ctr Invest Clin Morelia, Morelia, Michoacan, Mexico..
    Catoggio, Luis
    Hosp Italiano Buenos Aires, RA-1181 Buenos Aires, DF, Argentina..
    Cervera, Ricard
    Univ Barcelona, Hosp Clin, Dept Autoimmune Dis, Barcelona 08007, Catalonia, Spain..
    Cucho-Venegas, Jorge M.
    Univ Nacl Mayor San Marcos, Fac Med, Dept Reumatol, Lima 15081, Peru..
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, S-90187 Umea, Sweden..
    D'Alfonso, Sandra
    Univ Piemonte Orientale, Dept Hlth Sci & Inst Res Autoimmune Dis IRCAD, I-28100 Novara, Italy..
    Da Silva, Berta Martins
    Univ Porto, Inst Ciencias Biomed Abel Salaza, Unidade Multidisciplinar Invest Biomed, P-4099003 Oporto, Portugal..
    de la Rua Figueroa, Inigo
    Hosp Univ Gran Canaria Dr Negrin, Dept Rheumatol, Las Palmas Gran Canaria 35010, Spain..
    Doria, Andrea
    Univ Padua, Dept Med DIMED, Div Rheumatol, I-35122 Padua, Italy..
    Edberg, Jeffrey C.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Endreffy, Emoke
    Univ Szeged, Fac Med, Albert Szent Gyorgyi Med Ctr, Dept Pediat, H-6720 Szeged, Hungary.;Univ Szeged, Fac Med, Albert Szent Gyorgyi Med Ctr, Child Hlth Ctr, H-6720 Szeged, Hungary..
    Esquivel-Valerio, Jorge A.
    Hosp Univ Dr Jose Eleuterio Gonzalez Univ Autonom, Monterrey 64020, Mexico..
    Fortin, Paul R.
    Univ Laval, CHU Quebec, Quebec City, PQ G1R 2JG, Canada..
    Freedman, Barry I.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC 27101 USA..
    Frostegard, Johan
    Karolinska Inst, Inst Environm Med, Unit Immunol & Chron Dis, S-17177 Stockholm, Sweden..
    Garcia, Mercedes A.
    Hosp Interzonal Gen Agudos Gen San Martin, Div Rheumatol, RA-1900 La Plata, Buenos Aires, Argentina..
    Garcia de la Torre, Ignacio
    Univ Guadalajara, Dept Fisiol, Guadalajara, Jalisco 44100, Mexico..
    Gilkeson, Gary S.
    Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Gladman, Dafna D.
    Toronto Western Hosp, Krembil Res Inst, Ctr Prognosis Studies Rheumat Dis, Toronto, ON M5T 2S8, Canada..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Rheumatol Unit, S-17176 Stockholm, Sweden..
    Guthridge, Joel M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Huggins, Jennifer L.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Rheumatol, Cincinnati, OH 45229 USA.;Univ Cincinnati, Cincinnati, OH 45229 USA..
    James, Judith A.
    Hosp Eva Peron, Granadero Baigorria, Argentina.;Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA..
    Kallenberg, Cees G. M.
    Univ Med Ctr Groningen, Univ Groningen, Dept Rheumatol & Clin Immunol, NL-9713 GZ Groningen, Netherlands..
    Kamen, Diane L.
    Karp, David R.
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Kaufman, Kenneth M.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Kottyan, Leah C.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Kovacs, Laszlo
    Univ Szeged, Albert Szent Gyorgyi Med Ctr, Dept Rheumatol, H-6720 Szeged, Hungary..
    Laustrup, Helle
    Odense Univ Hosp, Dept Rheumatol, DK-5000 Odense, Denmark..
    Lauwerys, Bernard R.
    Catholic Univ Louvain, Clin Univ St Luc, Rheumatol, B-1348 Louvain La Neuve, Belgium.;Catholic Univ Louvain, Inst Rech Expt & Clin, B-1348 Louvain La Neuve, Belgium..
    Li, Quan-Zhen
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Maradiaga-Cecena, Marco A.
    Hosp Gen Culiacan, Sinaloa 80220, Mexico..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain..
    McCune, Joseph M.
    Univ Michigan, Med Ctr, Ann Arbor, MI 48103 USA..
    McWilliams, David R.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Merrill, Joan T.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Miranda, Pedro
    Ctr Estudios Reumatol, Santiago 7500000, Chile..
    Moctezuma, Jose F.
    Hosp Gen Mexico City, Dept Reumatol, Mexico City 06726, DF, Mexico..
    Nath, Swapan K.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Niewold, Timothy B.
    Mayo Clin, Dept Rheumatol, Rochester, MN 94158 USA..
    Orozco, Lorena
    Inst Nacl Med Genom INMEGEN, Mexico City 14610, DF, Mexico..
    Ortego-Centeno, Norberto
    Hosp Univ San Cecilio, UGC Med Interna, Unidad Enfermedades Autoimmunes Sistem, Granada 18007, Spain..
    Petri, Michelle
    Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21218 USA..
    Pineau, Christian A.
    McGill Univ, Div Rheumatol, Montreal, PQ H3A 0G4, Canada..
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Dept Rheumatol, Rosario, Santa Fe, Argentina..
    Pope, Janet
    Univ Western Ontario, London, ON M5T 2S8, Canada..
    Raj, Prithvi
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Ramsey-Goldman, Rosalind
    Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA..
    Reveille, John D.
    Univ Texas Hlth Sci Ctr Houston UTHealth, Med Sch, Houston, TX 77030 USA..
    Russell, Laurie P.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Sabio, Jose M.
    Hosp Univ Virgen de las Nieves, Granada 18014, Spain..
    Aguilar-Salinas, Carlos A.
    Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Vasco Quiroga 15, Mexico City 14080, DF, Mexico..
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Unidad Reumatol & Enfermedades, Buenos Aires, DF, Argentina..
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Referral Ctr Syst Autoimmune Dis, I-20122 Milan, Italy.;Univ Milan, I-20122 Milan, Italy..
    Seldin, Michael F.
    UC Davis Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95616 USA..
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Rheumatol Div Neuro & Inflammat Sci, S-58183 Linkoping, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Rheumatol Unit, S-17176 Stockholm, Sweden..
    Thompson, Susan D.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Toloza, Sergio M. A.
    Minist Hlth, Catamarca, Argentina..
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, S-22100 Lund, Sweden..
    Tusie-Luna, Teresa
    UNAM Inst Nacl Ciencias Med & Nutr Salvador Zubir, Inst Invest Biomed, Unidad Biol Mol & Med Genom, Mexico City 14080, DF, Mexico..
    Vasconcelos, Carlos
    Univ Porto, Hosp Santo Antonio, P-4099003 Oporto, Portugal..
    Vila, Luis M.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Wallace, Daniel J.
    Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA..
    Weisman, Michael H.
    Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA..
    Wither, Joan E.
    Toronto Western Hosp, Krembil Res Inst, Ctr Prognosis Studies Rheumat Dis, Toronto, ON M5T 2S8, Canada..
    Bhangale, Tushar
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Oksenberg, Jorge R.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA..
    Rioux, John D.
    Univ Montreal, Montreal, PQ H1T 1C8, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Gregersen, Peter K.
    Feinstein Inst Med Res, Ctr Genom Human Genet, Manhasset, NY 11030 USA..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Criswell, Lindsey A.
    UCSF Sch Med, Rosalind Russell Ephraim P Engleman Rheumatol Res, Div Rheumatol, San Francisco, CA 94158 USA..
    Jacob, Chaim O.
    Keck Sch Med USC, Los Angeles, CA 90033 USA..
    Sivils, Kathy L.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Tsao, Betty P.
    Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Schanberg, Laura E.
    Duke Univ, Dept Pediat, Durham, NC 27708 USA..
    Behrens, Timothy W.
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Silverman, Earl D.
    Hosp Sick Children, Res Inst, Dept Pediat, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Res Inst, Inst Med Sci, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Toronto, ON M5G 1X8, Canada..
    Alarcon-Riquelme, Marta E.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA.;Univ Granada, Pfizer, Junta De Andalucia Ctr Genom & Oncol Res GENYO, Granada 18007, Spain.;Karolinska Inst, Unit Inst Environm Med, S-17177 Solnavagen, Sweden..
    Kimberly, Robert P.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Harley, John B.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Wakeland, Edward K.
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Graham, Robert R.
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Gaffney, Patrick M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Vyse, Timothy J.
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Transancestral mapping and genetic load in systemic lupus erythematosus2017In: Nature Communications, E-ISSN 2041-1723, Vol. 8, article id 16021Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

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  • 147. Lappalainen, Tuuli
    et al.
    Sammeth, Michael
    Friedländer, Marc R
    't Hoen, Peter A C
    Monlong, Jean
    Rivas, Manuel A
    Gonzàlez-Porta, Mar
    Kurbatova, Natalja
    Griebel, Thasso
    Ferreira, Pedro G
    Barann, Matthias
    Wieland, Thomas
    Greger, Liliana
    van Iterson, Maarten
    Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ribeca, Paolo
    Pulyakhina, Irina
    Esser, Daniela
    Giger, Thomas
    Tikhonov, Andrew
    Sultan, Marc
    Bertier, Gabrielle
    Macarthur, Daniel G
    Lek, Monkol
    Lizano, Esther
    Buermans, Henk P J
    Padioleau, Ismael
    Schwarzmayr, Thomas
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ongen, Halit
    Kilpinen, Helena
    Beltran, Sergi
    Gut, Marta
    Kahlem, Katja
    Amstislavskiy, Vyacheslav
    Stegle, Oliver
    Pirinen, Matti
    Montgomery, Stephen B
    Donnelly, Peter
    McCarthy, Mark I
    Flicek, Paul
    Strom, Tim M
    Lehrach, Hans
    Schreiber, Stefan
    Sudbrak, Ralf
    Carracedo, Angel
    Antonarakis, Stylianos E
    Häsler, Robert
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Ommen, Gert-Jan
    Brazma, Alvis
    Meitinger, Thomas
    Rosenstiel, Philip
    Guigó, Roderic
    Gut, Ivo G
    Estivill, Xavier
    Dermitzakis, Emmanouil T
    Transcriptome and genome sequencing uncovers functional variation in humans2013In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, no 7468, p. 506-511Article in journal (Refereed)
    Abstract [en]

    Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

  • 148.
    Leonard, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    Sandling, Johanna K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Jönsen, Andreas
    Bengtsson, Christine
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jensen-Urstad, Kerstin
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Bengtsson, Anders A
    Gustafsson, Johanna T
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants2013In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 6, no 3, p. 255-263Article in journal (Refereed)
    Abstract [en]

    Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.

  • 149.
    Liljedahl, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Fredriksson, Mona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Dahlgren, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Detecting imbalanced expression of SNP alleles by minisequencing on microarrays2004In: BMC Biotechnology, E-ISSN 1472-6750, Vol. 4, no 24, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Each of the human genes or transcriptional units is likely to contain single nucleotide polymorphisms that may give rise to sequence variation between individuals and tissues on the level of RNA. Based on recent studies, differential expression of the two alleles of heterozygous coding single nucleotide polymorphisms (SNPs) may be frequent for human genes. Methods with high accuracy to be used in a high throughput setting are needed for systematic surveys of expressed sequence variation. In this study we evaluated two formats of multiplexed, microarray based minisequencing for quantitative detection of imbalanced expression of SNP alleles. We used a panel of ten SNPs located in five genes known to be expressed in two endothelial cell lines as our model system.

    RESULTS:

    The accuracy and sensitivity of quantitative detection of allelic imbalance was assessed for each SNP by constructing regression lines using a dilution series of mixed samples from individuals of different genotype. Accurate quantification of SNP alleles by both assay formats was evidenced for by R2 values > 0.95 for the majority of the regression lines. According to a two sample t-test, we were able to distinguish 1-9% of a minority SNP allele from a homozygous genotype, with larger variation between SNPs than between assay formats. Six of the SNPs, heterozygous in either of the two cell lines, were genotyped in RNA extracted from the endothelial cells. The coefficient of variation between the fluorescent signals from five parallel reactions was similar for cDNA and genomic DNA. The fluorescence signal intensity ratios measured in the cDNA samples were compared to those in genomic DNA to determine the relative expression levels of the two alleles of each SNP. Four of the six SNPs tested displayed a higher than 1.4-fold difference in allelic ratios between cDNA and genomic DNA. The results were verified by allele-specific oligonucleotide hybridisation and minisequencing in a microtiter plate format.

    CONCLUSIONS:

    We conclude that microarray based minisequencing is an accurate and accessible tool for multiplexed screening for imbalanced allelic expression in multiple samples and tissues in parallel.

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  • 150.
    Liljedahl, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Fredriksson, Mona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Analysis of DNA sequence variation in the microarray format2005In: Microarray Technology and Its Applications / [ed] U R Müller & Dan V Nicolau, Berlin: Springer, 2005, p. 211-227Chapter in book (Other (popular science, discussion, etc.))
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