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  • 1. Agler, Caryline
    et al.
    Nielsen, Dahlia M.
    Urkasemsin, Ganokon
    Singleton, Andrew
    Tonomura, Noriko
    Sigurdsson, Snaevar
    Tang, Ruqi
    Linder, Keith
    Arepalli, Sampath
    Hernandez, Dena
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van de Leemput, Joyce
    Motsinger-Reif, Alison
    O'Brien, Dennis P.
    Bell, Jerold
    Harris, Tonya
    Steinberg, Steven
    Olby, Natasha J.
    Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB242014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1003991-Article in journal (Refereed)
    Abstract [en]

    Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.

  • 2. Ahmad, Shafqat
    et al.
    Rukh, Gull
    Varga, Tibor V.
    Ali, Ashfaq
    Kurbasic, Azra
    Shungin, Dmitry
    Ericson, Ulrika
    Koivula, Robert W.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ganna, Andrea
    Qi, Qibin
    Stancakova, Alena
    Sandholt, Camilla H.
    Elks, Cathy E.
    Curhan, Gary
    Jensen, Majken K.
    Tamimi, Rulla M.
    Allin, Kristine H.
    Jorgensen, Torben
    Brage, Soren
    Langenberg, Claudia
    Aadahl, Mette
    Grarup, Niels
    Linneberg, Allan
    Pare, Guillaume
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Boehnke, Michael
    Hamsten, Anders
    Mohlke, Karen L.
    Pasquale, Louis T.
    Pedersen, Oluf
    Scott, Robert A.
    Ridker, Paul M.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Laakso, Markku
    Hansen, Torben
    Qi, Lu
    Wareham, Nicholas J.
    Chasman, Daniel I.
    Hallmans, Goran
    Hu, Frank B.
    Renstrom, Frida
    Orho-Melander, Marju
    Franks, Paul W.
    Gene x Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 7, p. e1003607-Article in journal (Refereed)
    Abstract [en]

    Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS x physical activity interaction effect estimate (P-interaction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, P-interaction = 0.014 vs. n = 71,611, P-interaction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (P-interaction = 0.003) and the SEC16B rs10913469 (P-interaction = 0.025) variants showed evidence of SNP x physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.

  • 3. Bjorkegren, Johan L. M.
    et al.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Talukdar, Husain A.
    Asl, Hassan Foroughi
    Jain, Rajeev K.
    Cedergren, Cecilia
    Shang, Ming-Mei
    Rossignoli, Aranzazu
    Takolander, Rabbe
    Melander, Olle
    Hamsten, Anders
    Michoel, Tom
    Skogsberg, Josefin
    Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e100420-Article in journal (Refereed)
    Abstract [en]

    Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (>= 80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob(100/100)Mttp(flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. Author Summary The main underlying cause of heart attacks and strokes is atherosclerosis. One strategy to prevent these often deadly clinical events is therefore either to slow atherosclerosis progression or better, induce regression of atherosclerotic plaques making them more stable. Plasma cholesterol lowering (PCL) is the most efficient way to induce atherosclerosis regression but sometimes fails to do so. In our study, we used a mouse model with elevated LDL cholesterol levels, similar to humans who develop early atherosclerosis, and a genetic switch to lower plasma cholesterol at any time during atherosclerosis progression. In this model, we examined atherosclerosis gene expression and regression in response to PCL at three different stages of atherosclerosis progression. PCL led to complete regression in mice with early lesions but was incomplete in mice with mature and advanced lesions, indicating that early prevention with PCL in individuals with increased risk for heart attack or stroke would be particularly useful. In addition, by inferring PCL-responsive gene networks in early, mature and advanced atherosclerotic lesions, we identified key drivers specific for regression of early (PPARG), mature (MLL5) and advanced (SRSF10/XRN2) atherosclerosis. These key drivers should be interesting therapeutic targets to enhance PCL-mediated regression of atherosclerosis.

  • 4. Bolton, Jennifer L.
    et al.
    Hayward, Caroline
    Direk, Nese
    Lewis, John G.
    Hammond, Geoffrey L.
    Hill, Lesley A.
    Anderson, Anna
    Huffman, Jennifer
    Wilson, James F.
    Campbell, Harry
    Rudan, Igor
    Wright, Alan
    Hastie, Nicholas
    Wild, Sarah H.
    Velders, Fleur P.
    Hofman, Albert
    Uitterlinden, Andre G.
    Lahti, Jari
    Raikkonen, Katri
    Kajantie, Eero
    Widen, Elisabeth
    Palotie, Aarno
    Eriksson, Johan G.
    Kaakinen, Marika
    Jarvelin, Marjo-Riitta
    Timpson, Nicholas J.
    Smith, George Davey
    Ring, Susan M.
    Evans, David M.
    St Pourcain, Beate
    Tanaka, Toshiko
    Milaneschi, Yuri
    Bandinelli, Stefania
    Ferrucci, Luigi
    van der Harst, Pim
    Rosmalen, Judith G. M.
    Bakker, Stephen J. L.
    Verweij, Niek
    Dullaart, Robin P. F.
    Mahajan, Anubha
    Lindgren, Cecilia M.
    Morris, Andrew
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Anderson, Laura N.
    Pennell, Craig E.
    Lye, Stephen J.
    Matthews, Stephen G.
    Eriksson, Joel
    Mellstrom, Dan
    Ohlsson, Claes
    Price, Jackie F.
    Strachan, Mark W. J.
    Reynolds, Rebecca M.
    Tiemeier, Henning
    Walker, Brian R.
    Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding alpha 1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

  • 5. Brandvain, Yaniv
    et al.
    Slotte, Tanja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hazzouri, Khaled M.
    Wright, Stephen I.
    Coop, Graham
    Genomic Identification of Founding Haplotypes Reveals the History of the Selfing Species Capsella rubella2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 9, p. e1003754-Article in journal (Refereed)
    Abstract [en]

    The shift from outcrossing to self-fertilization is among the most common evolutionary transitions in flowering plants. Until recently, however, a genome-wide view of this transition has been obscured by both a dearth of appropriate data and the lack of appropriate population genomic methods to interpret such data. Here, we present a novel population genomic analysis detailing the origin of the selfing species, Capsella rubella, which recently split from its outcrossing sister, Capsella grandiflora. Due to the recency of the split, much of the variation within C. rubella is also found within C. grandiflora. We can therefore identify genomic regions where two C. rubella individuals have inherited the same or different segments of ancestral diversity (i.e. founding haplotypes) present in C. rubella's founder(s). Based on this analysis, we show that C. rubella was founded by multiple individuals drawn from a diverse ancestral population closely related to extant C. grandiflora, that drift and selection have rapidly homogenized most of this ancestral variation since C. rubella's founding, and that little novel variation has accumulated within this time. Despite the extensive loss of ancestral variation, the approximately 25% of the genome for which two C. rubella individuals have inherited different founding haplotypes makes up roughly 90% of the genetic variation between them. To extend these findings, we develop a coalescent model that utilizes the inferred frequency of founding haplotypes and variation within founding haplotypes to estimate that C. rubella was founded by a potentially large number of individuals between 50 and 100 kya, and has subsequently experienced a twenty-fold reduction in its effective population size. As population genomic data from an increasing number of outcrossing/selfing pairs are generated, analyses like the one developed here will facilitate a fine-scaled view of the evolutionary and demographic impact of the transition to self-fertilization.

  • 6. Couch, Fergus J.
    et al.
    Wang, Xianshu
    McGuffog, Lesley
    Lee, Andrew
    Olswold, Curtis
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Fredericksen, Zachary
    Barrowdale, Daniel
    Dennis, Joe
    Gaudet, Mia M.
    Dicks, Ed
    Kosel, Matthew
    Healey, Sue
    Sinilnikova, Olga M.
    Lee, Adam
    Bacot, Francois
    Vincent, Daniel
    Hogervorst, Frans B. L.
    Peock, Susan
    Stoppa-Lyonnet, Dominique
    Jakubowska, Anna
    Radice, Paolo
    Schmutzler, Rita Katharina
    Domchek, Susan M.
    Piedmonte, Marion
    Singer, Christian F.
    Friedman, Eitan
    Thomassen, Mads
    Hansen, Thomas V. O.
    Neuhausen, Susan L.
    Szabo, Csilla I.
    Blanco, Ignacio
    Greene, Mark H.
    Karlan, Beth Y.
    Garber, Judy
    Phelan, Catherine M.
    Weitzel, Jeffrey N.
    Montagna, Marco
    Olah, Edith
    Andrulis, Irene L.
    Godwin, Andrew K.
    Yannoukakos, Drakoulis
    Goldgar, David E.
    Caldes, Trinidad
    Nevanlinna, Heli
    Osorio, Ana
    Terry, Mary Beth
    Daly, Mary B.
    van Rensburg, Elizabeth J.
    Hamann, Ute
    Ramus, Susan J.
    Toland, Amanda Ewart
    Caligo, Maria A.
    Olopade, Olufunmilayo I.
    Tung, Nadine
    Claes, Kathleen
    Beattie, Mary S.
    Southey, Melissa C.
    Imyanitov, Evgeny N.
    Tischkowitz, Marc
    Janavicius, Ramunas
    John, Esther M.
    Kwong, Ava
    Diez, Orland
    Balmana, Judith
    Barkardottir, Rosa B.
    Arun, Banu K.
    Rennert, Gad
    Teo, Soo-Hwang
    Ganz, Patricia A.
    Campbell, Ian
    van der Hout, Annemarie H.
    van Deurzen, Carolien H. M.
    Seynaeve, Caroline
    Garcia, Encarna B. Gomez
    van Leeuwen, Flora E.
    Meijers-Heijboer, Hanne E. J.
    Gille, Johannes J. P.
    Ausems, Margreet G. E. M.
    Blok, Marinus J.
    Ligtenberg, Marjolijn J. L.
    Rookus, Matti A.
    Devilee, Peter
    Verhoef, Senno
    van Os, Theo A. M.
    Wijnen, Juul T.
    Frost, Debra
    Ellis, Steve
    Fineberg, Elena
    Platte, Radka
    Evans, D. Gareth
    Izatt, Louise
    Eeles, Rosalind A.
    Adlard, Julian
    Eccles, Diana M.
    Cook, Jackie
    Brewer, Carole
    Douglas, Fiona
    Hodgson, Shirley
    Morrison, Patrick J.
    Side, Lucy E.
    Donaldson, Alan
    Houghton, Catherine
    Rogers, Mark T.
    Dorkins, Huw
    Eason, Jacqueline
    Gregory, Helen
    McCann, Emma
    Murray, Alex
    Calender, Alain
    Hardouin, Agnes
    Berthet, Pascaline
    Delnatte, Capucine
    Nogues, Catherine
    Lasset, Christine
    Houdayer, Claude
    Leroux, Dominique
    Rouleau, Etienne
    Prieur, Fabienne
    Damiola, Francesca
    Sobol, Hagay
    Coupier, Isabelle
    Venat-Bouvet, Laurence
    Castera, Laurent
    Gauthier-Villars, Marion
    Leone, Melanie
    Pujol, Pascal
    Mazoyer, Sylvie
    Bignon, Yves-Jean
    Zlowocka-Perlowska, Elzbieta
    Gronwald, Jacek
    Lubinski, Jan
    Durda, Katarzyna
    Jaworska, Katarzyna
    Huzarski, Tomasz
    Spurdle, Amanda B.
    Viel, Alessandra
    Peissel, Bernard
    Bonanni, Bernardo
    Melloni, Giulia
    Ottini, Laura
    Papi, Laura
    Varesco, Liliana
    Tibiletti, Maria Grazia
    Peterlongo, Paolo
    Volorio, Sara
    Manoukian, Siranoush
    Pensotti, Valeria
    Arnold, Norbert
    Engel, Christoph
    Deissler, Helmut
    Gadzicki, Dorothea
    Gehrig, Andrea
    Kast, Karin
    Rhiem, Kerstin
    Meindl, Alfons
    Niederacher, Dieter
    Ditsch, Nina
    Plendl, Hansjoerg
    Preisler-Adams, Sabine
    Engert, Stefanie
    Sutter, Christian
    Varon-Mateeva, Raymonda
    Wappenschmidt, Barbara
    Weber, Bernhard H. F.
    Arver, Brita
    Stenmark-Askmalm, Marie
    Loman, Niklas
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Einbeigi, Zakaria
    Nathanson, Katherine L.
    Rebbeck, Timothy R.
    Blank, Stephanie V.
    Cohn, David E.
    Rodriguez, Gustavo C.
    Small, Laurie
    Friedlander, Michael
    Bae-Jump, Victoria L.
    Fink-Retter, Anneliese
    Rappaport, Christine
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Tea, Muy-Kheng
    Lindor, Noralane M.
    Kaufman, Bella
    Paluch, Shani Shimon
    Laitman, Yael
    Skytte, Anne-Bine
    Gerdes, Anne-Marie
    Pedersen, Inge Sokilde
    Moeller, Sanne Traasdahl
    Kruse, Torben A.
    Jensen, Uffe Birk
    Vijai, Joseph
    Sarrel, Kara
    Robson, Mark
    Kauff, Noah
    Mulligan, Anna Marie
    Glendon, Gord
    Ozcelik, Hilmi
    Ejlertsen, Bent
    Nielsen, Finn C.
    Jonson, Lars
    Andersen, Mette K.
    Ding, Yuan Chun
    Steele, Linda
    Foretova, Lenka
    Teule, Alex
    Lazaro, Conxi
    Brunet, Joan
    Angel Pujana, Miquel
    Mai, Phuong L.
    Loud, Jennifer T.
    Walsh, Christine
    Lester, Jenny
    Orsulic, Sandra
    Narod, Steven A.
    Herzog, Josef
    Sand, Sharon R.
    Tognazzo, Silvia
    Agata, Simona
    Vaszko, Tibor
    Weaver, Joellen
    Stavropoulou, Alexandra V.
    Buys, Saundra S.
    Romero, Atocha
    de la Hoya, Miguel
    Aittomaki, Kristiina
    Muranen, Taru A.
    Duran, Mercedes
    Chung, Wendy K.
    Lasa, Adriana
    Dorfling, Cecilia M.
    Miron, Alexander
    Benitez, Javier
    Senter, Leigha
    Huo, Dezheng
    Chan, Salina B.
    Sokolenko, Anna P.
    Chiquette, Jocelyne
    Tihomirova, Laima
    Friebel, Tara M.
    Agnarsson, Bjarni A.
    Lu, Karen H.
    Lejbkowicz, Flavio
    James, Paul A.
    Hall, Per
    Dunning, Alison M.
    Tessier, Daniel
    Cunningham, Julie
    Slager, Susan L.
    Wang, Chen
    Hart, Steven
    Stevens, Kristen
    Simard, Jacques
    Pastinen, Tomi
    Pankratz, Vernon S.
    Offit, Kenneth
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3, p. e1003212-Article in journal (Refereed)
    Abstract [en]

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  • 7. Coviello, Andrea D.
    et al.
    Haring, Robin
    Wellons, Melissa
    Vaidya, Dhananjay
    Lehtimaki, Terho
    Keildson, Sarah
    Lunetta, Kathryn L.
    He, Chunyan
    Fornage, Myriam
    Lagou, Vasiliki
    Mangino, Massimo
    Onland-Moret, N. Charlotte
    Chen, Brian
    Eriksson, Joel
    Garcia, Melissa
    Mei, Yong
    Koster, Annemarie
    Lohman, Kurt
    Lyytikainen, Leo-Pekka
    Petersen, Ann-Kristin
    Prescott, Jennifer
    Stolk, Lisette
    Vandenput, Liesbeth
    Wood, Andrew R.
    Zhuang, Wei Vivian
    Ruokonen, Aimo
    Hartikainen, Anna-Liisa
    Pouta, Anneli
    Bandinelli, Stefania
    Biffar, Reiner
    Brabant, Georg
    Cox, David G.
    Chen, Yuhui
    Cummings, Steven
    Ferrucci, Luigi
    Gunter, Marc J.
    Hankinson, Susan E.
    Martikainen, Hannu
    Hofman, Albert
    Homuth, Georg
    Illig, Thomas
    Jansson, John-Olov
    Johnson, Andrew D.
    Karasik, David
    Karlsson, Magnus
    Kettunen, Johannes
    Kiel, Douglas P.
    Kraft, Peter
    Liu, Jingmin
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Lorentzon, Mattias
    Maggio, Marcello
    Markus, Marcello R. P.
    Mellstrom, Dan
    Miljkovic, Iva
    Mirel, Daniel
    Nelson, Sarah
    Papunen, Laure Morin
    Peeters, Petra H. M.
    Prokopenko, Inga
    Raffel, Leslie
    Reincke, Martin
    Reiner, Alex P.
    Rexrode, Kathryn
    Rivadeneira, Fernando
    Schwartz, Stephen M.
    Siscovick, David
    Soranzo, Nicole
    Stockl, Doris
    Tworoger, Shelley
    Uitterlinden, Andre G.
    van Gils, Carla H.
    Vasan, Ramachandran S.
    Wichmann, H. -Erich
    Zhai, Guangju
    Bhasin, Shalender
    Bidlingmaier, Martin
    Chanock, Stephen J.
    De Vivo, Immaculata
    Harris, Tamara B.
    Hunter, David J.
    Kahonen, Mika
    Liu, Simin
    Ouyang, Pamela
    Spector, Tim D.
    van der Schouw, Yvonne T.
    Viikari, Jorma
    Wallaschofski, Henri
    McCarthy, Mark I.
    Frayling, Timothy M.
    Murray, Anna
    Franks, Steve
    Jarvelin, Marjo-Riitta
    de Jong, Frank H.
    Raitakari, Olli
    Teumer, Alexander
    Ohlsson, Claes
    Murabito, Joanne M.
    Perry, John R. B.
    A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone-Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 7, p. e1002805-Article in journal (Refereed)
    Abstract [en]

    Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8x10(-106)), PRMT6 (rs17496332, 1p13.3, p=1.4x10(-11)), GCKR (rs780093, 2p23.3, p=2.2x10(-16)), ZBTB10 (rs440837, 8q21.13, p=3.4x10(-09)), JMJD1C (rs7910927, 10q21.3, p=6.1x10(-35)), SLCO1B1 (rs4149056, 12p12.1, p=1.9x10(-08)), NR2F2 (rs8023580, 15q26.2, p=8.3x10(-12)), ZNF652 (rs2411984, 17q21.32, p=3.5x10(-14)), TDGF3 (rs1573036, Xq22.3, p=4.1x10(-14)), LHCGR (rs10454142, 2p16.3, p=1.3x10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p=2.7x10(-08)), and UGT2B15 (rs293428, 4q13.2, p=5.5x10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5x10(-08), women p=0.66, heterogeneity p=0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained similar to 15.6% and similar to 8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

  • 8. Curik, Ino
    et al.
    Druml, Thomas
    Seltenhammer, Monika
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Solkner, Johann
    Complex Inheritance of Melanoma and Pigmentation of Coat and Skin in Grey Horses2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 2, p. e1003248-Article in journal (Refereed)
    Abstract [en]

    The dominant phenotype of greying with age in horses, caused by a 4.6-kb duplication in intron 6 of STX17, is associated with a high incidence of melanoma and vitiligo-like skin depigmentation. However, the progressive greying and the incidence of melanoma, vitiligo-like depigmentation, and amount of speckling in these horses do not follow a simple inheritance pattern. To understand their inheritance, we analysed the melanoma grade, grey level, vitiligo grade, and speckling grade of 1,119 Grey horses (7,146 measurements) measured in six countries over a 9-year period. We estimated narrow sense heritability (h(2)), and we decomposed this parameter into polygenic heritability (h(POLY)(2)), heritability due to the Grey (STX17) mutation (h(STX17)(2)), and heritability due to agouti (ASIP) locus (h(ASIP)(2)). A high heritability was found for greying (h(2) = 0.79), vitiligo (h(2) = 0.63), and speckling (h(2) = 0.66), while a moderate heritability was estimated for melanoma (h(2) = 0.37). The additive component of ASIP was significantly different from zero only for melanoma (h(ASIP)(2) = 0.02). STX17 controlled large proportions of phenotypic variance (h(STX17)(2) = 0.18-0.55) and overall heritability (h(STX17)(2)/h(2) = 0.28-0.83) for all traits. Genetic correlations among traits were estimated as moderate to high, primarily due to the effects of the STX17 locus. Nevertheless, the correlation between progressive greying and vitiligo-like depigmentation remained large even after taking into account the effects of STX17. We presented a model where four traits with complex inheritance patterns are strongly influenced by a single mutation. This is in line with evidence of recent studies in domestic animals indicating that some complex traits are, in addition to the large number of genes with small additive effects, influenced by genes of moderate-to-large effect. Furthermore, we demonstrated that the STX17 mutation explains to a large extent the moderate to high genetic correlations among traits, providing an example of strong pleiotropic effects caused by a single gene.

  • 9. Dastani, Zari
    et al.
    Hivert, Marie-France
    Timpson, Nicholas
    Perry, John R. B.
    Yuan, Xin
    Scott, Robert A.
    Henneman, Peter
    Heid, Iris M.
    Kizer, Jorge R.
    Lyytikainen, Leo-Pekka
    Fuchsberger, Christian
    Tanaka, Toshiko
    Morris, Andrew P.
    Small, Kerrin
    Isaacs, Aaron
    Beekman, Marian
    Coassin, Stefan
    Lohman, Kurt
    Qi, Lu
    Kanoni, Stavroula
    Pankow, James S.
    Uh, Hae-Won
    Wu, Ying
    Bidulescu, Aurelian
    Rasmussen-Torvik, Laura J.
    Greenwood, Celia M. T.
    Ladouceur, Martin
    Grimsby, Jonna
    Manning, Alisa K.
    Liu, Ching-Ti
    Kooner, Jaspal
    Mooser, Vincent E.
    Vollenweider, Peter
    Kapur, Karen A.
    Chambers, John
    Wareham, Nicholas J.
    Langenberg, Claudia
    Frants, Rune
    Willems-vanDijk, Ko
    Oostra, Ben A.
    Willems, Sara M.
    Lamina, Claudia
    Winkler, Thomas W.
    Psaty, Bruce M.
    Tracy, Russell P.
    Brody, Jennifer
    Chen, Ida
    Viikari, Jorma
    Kahonen, Mika
    Pramstaller, Peter P.
    Evans, David M.
    St Pourcain, Beate
    Sattar, Naveed
    Wood, Andrew R.
    Bandinelli, Stefania
    Carlson, Olga D.
    Egan, Josephine M.
    Bohringer, Stefan
    van Heemst, Diana
    Kedenko, Lyudmyla
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Loo, Britt-Marie
    Harris, Tamara
    Garcia, Melissa
    Kanaya, Alka
    Haun, Margot
    Klopp, Norman
    Wichmann, H. -Erich
    Deloukas, Panos
    Katsareli, Efi
    Couper, David J.
    Duncan, Bruce B.
    Kloppenburg, Margreet
    Adair, Linda S.
    Borja, Judith B.
    Wilson, James G.
    Musani, Solomon
    Guo, Xiuqing
    Johnson, Toby
    Semple, Robert
    Teslovich, Tanya M.
    Allison, Matthew A.
    Redline, Susan
    Buxbaum, Sarah G.
    Mohlke, Karen L.
    Meulenbelt, Ingrid
    Ballantyne, Christie M.
    Dedoussis, George V.
    Hu, Frank B.
    Liu, Yongmei
    Paulweber, Bernhard
    Spector, Timothy D.
    Slagboom, P. Eline
    Ferrucci, Luigi
    Jula, Antti
    Perola, Markus
    Raitakari, Olli
    Florez, Jose C.
    Salomaa, Veikko
    Eriksson, Johan G.
    Frayling, Timothy M.
    Hicks, Andrew A.
    Lehtimaki, Terho
    Smith, George Davey
    Siscovick, David S.
    Kronenberg, Florian
    van Duijn, Cornelia
    Loos, Ruth J. F.
    Waterworth, Dawn M.
    Meigs, James B.
    Dupuis, Josee
    Richards, J. Brent
    Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 3, p. e1002607-Article in journal (Refereed)
    Abstract [en]

    Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P=4.5 x 10(-8)-1.2 x 10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3 x 10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p=4.3 x 10(-3), n = 22,044), increased triglycerides (p=2.6 x 10(-14), n = 93,440), increased waist-to-hip ratio (p=1.8 x 10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p=4.4 x 10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p=4.5x10(-13), n = 96,748) and decreased BMI (p= 1.4 x 10(-14), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

  • 10.
    Dean, Rebecca
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Perry, Jennifer C.
    Pizzari, Tommaso
    Mank, Judith E.
    Wigby, Stuart
    Experimental Evolution of a Novel Sexually Antagonistic Allele2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 8, p. e1002917-Article in journal (Refereed)
    Abstract [en]

    Evolutionary conflict permeates biological systems. In sexually reproducing organisms, sex-specific optima mean that the same allele can have sexually antagonistic expression, i.e. beneficial in one sex and detrimental in the other, a phenomenon known as intralocus sexual conflict. Intralocus sexual conflict is emerging as a potentially fundamental factor for the genetic architecture of fitness, with important consequences for evolutionary processes. However, no study to date has directly experimentally tested the evolutionary fate of a sexually antagonistic allele. Using genetic constructs to manipulate female fecundity and male mating success, we engineered a novel sexually antagonistic allele (SAA) in Drosophila melanogaster. The SAA is nearly twice as costly to females as it is beneficial to males, but the harmful effects to females are recessive and X-linked, and thus are rarely expressed when SAA occurs at low frequency. We experimentally show how the evolutionary dynamics of the novel SAA are qualitatively consistent with the predictions of population genetic models: SAA frequency decreases when common, but increases when rare, converging toward an equilibrium frequency of similar to 8%. Furthermore, we show that persistence of the SAA requires the mating advantage it provides to males: the SAA frequency declines towards extinction when the male advantage is experimentally abolished. Our results empirically demonstrate the dynamics underlying the evolutionary fate of a sexually antagonistic allele, validating a central assumption of intralocus sexual conflict theory: that variation in fitness-related traits within populations can be maintained via sex-linked sexually antagonistic loci.

  • 11.
    Dorshorst, Ben
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Bagherpoor, Alireza Jian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ashwell, Chris
    Gourichon, David
    Tixier-Boichard, Michèle
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A Genomic Duplication is Associated with Ectopic Eomesodermin Expression in the Embryonic Chicken Comb and Two Duplex-comb Phenotypes2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, article id e1004947Article in journal (Refereed)
    Abstract [en]

    Duplex-comb (D) is one of three major loci affecting comb morphology in the domestic chicken. Here we show that the two Duplex-comb alleles, V-shaped (D*V) and Buttercup (D*C), are both associated with a 20 Kb tandem duplication containing several conserved putative regulatory elements located 200 Kb upstream of the eomesodermin gene (EOMES). EOMES is a T-box transcription factor that is involved in mesoderm specification during gastrulation. In D*V and D*C chicken embryos we find that EOMES is ectopically expressed in the ectoderm of the comb-developing region as compared to wild-type embryos. The confinement of the ectopic expression of EOMES to the ectoderm is in stark contrast to the causal mechanisms underlying the two other major comb loci in the chicken (Rose-comb and Pea-comb) in which the transcription factors MNR2 and SOX5 are ectopically expressed strictly in the mesenchyme. Interestingly, the causal mutations of all three major comb loci in the chicken are now known to be composed of large-scale structural genomic variants that each result in ectopic expression of transcription factors. The Duplex-comb locus also illustrates the evolution of alleles in domestic animals, which means that alleles evolve by the accumulation of two or more consecutive mutations affecting the phenotype. We do not yet know whether the V-shaped or Buttercup allele correspond to the second mutation that occurred on the haplotype of the original duplication event.

  • 12.
    Ellegaard, Kirsten Maren
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klasson, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bourtzis, Kostas
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comparative Genomics of Wolbachia and the Bacterial Species Concept2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 4, p. e1003381-Article in journal (Refereed)
    Abstract [en]

    The importance of host-specialization to speciation processes in obligate host-associated bacteria is well known, as is also the ability of recombination to generate cohesion in bacterial populations. However, whether divergent strains of highly recombining intracellular bacteria, such as Wolbachia, can maintain their genetic distinctness when infecting the same host is not known. We first developed a protocol for the genome sequencing of uncultivable endosymbionts. Using this method, we have sequenced the complete genomes of the Wolbachia strains wHa and wNo, which occur as natural double infections in Drosophila simulans populations on the Seychelles and in New Caledonia. Taxonomically, wHa belong to supergroup A and wNo to supergroup B. A comparative genomics study including additional strains supported the supergroup classification scheme and revealed 24 and 33 group-specific genes, putatively involved in host-adaptation processes. Recombination frequencies were high for strains of the same supergroup despite different host-preference patterns, leading to genomic cohesion. The inferred recombination fragments for strains of different supergroups were of short sizes, and the genomes of the co-infecting Wolbachia strains wHa and wNo were not more similar to each other and did not share more genes than other A- and B-group strains that infect different hosts. We conclude that Wolbachia strains of supergroup A and B represent genetically distinct clades, and that strains of different supergroups can co-exist in the same arthropod host without converging into the same species. This suggests that the supergroups are irreversibly separated and that barriers other than host-specialization are able to maintain distinct clades in recombining endosymbiont populations. Acquiring a good knowledge of the barriers to genetic exchange in Wolbachia will advance our understanding of how endosymbiont communities are constructed from vertically and horizontally transmitted genes.

  • 13. Feng, Chungang
    et al.
    Gao, Yu
    Dorshorst, Ben
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Song, Chi
    Gu, Xiaorong
    Li, Qingyuan
    Li, Jinxiu
    Liu, Tongxin
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhao, Yiqiang
    Wang, Yanqiang
    Fei, Jing
    Li, Huifang
    Chen, Kuanwei
    Qu, Hao
    Shu, Dingming
    Ashwell, Chris
    Da, Yang
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hu, Xiaoxiang
    Li, Ning
    A cis-Regulatory Mutation of PDSS2 Causes Silky-Feather in Chickens2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 8, p. e1004576-Article in journal (Refereed)
    Abstract [en]

    Silky-feather has been selected and fixed in some breeds due to its unique appearance. This phenotype is caused by a single recessive gene (hookless, h). Here we map the silky-feather locus to chromosome 3 by linkage analysis and subsequently fine-map it to an 18.9 kb interval using the identical by descent (IBD) method. Further analysis reveals that a C to G transversion located upstream of the prenyl (decaprenyl) diphosphate synthase, subunit 2 (PDSS2) gene is causing silky-feather. All silky-feather birds are homozygous for the G allele. The silky-feather mutation significantly decreases the expression of PDSS2 during feather development in vivo. Consistent with the regulatory effect, the C to G transversion is shown to remarkably reduce PDSS2 promoter activity in vitro. We report a new example of feather structure variation associated with a spontaneous mutation and provide new insight into the PDSS2 function.

  • 14. Flores-Sandoval, Eduardo
    et al.
    Eklund, D. Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Bowman, John L.
    A simple auxin transcriptional response system regulates multiple morphogenetic processes in the liverwort Marchantia polymorpha2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 5, article id e1005207Article in journal (Refereed)
    Abstract [en]

    In land plants comparative genomics has revealed that members of basal lineages share a common set of transcription factors with the derived flowering plants, despite sharing few homologous structures. The plant hormone auxin has been implicated in many facets of development in both basal and derived lineages of land plants. We functionally characterized the auxin transcriptional response machinery in the liverwort Marchantia polymorpha, a member of the basal lineage of extant land plants. All components known from flowering plant systems are present in Mpolymorpha, but they exist as single orthologs: a singleMpTOPLESS (TPL) corepressor, a single MpTRANSPORT INHIBITOR RESPONSE 1 auxin receptor, single orthologs of each class of AUXIN RESPONSE FACTOR (ARF; MpARF1,MpARF2MpARF3), and a single negative regulator AUXIN/INDOLE-3-ACETIC ACID (MpIAA). Phylogenetic analyses suggest this simple system is the ancestral condition for land plants. We experimentally demonstrate that these genes act in an auxin response pathway — chimeric fusions of the MpTPL corepressor with heterodimerization domains of MpARF1, MpARF2, or their negative regulator, MpIAA, generate auxin insensitive plants that lack the capacity to pattern and transition into mature stages of development. Our results indicate auxin mediated transcriptional regulation acts as a facilitator of branching, differentiation and growth, rather than acting to determine or specify tissues during the haploid stage of the M.polymorpha life cycle. We hypothesize that the ancestral role of auxin is to modulate a balance of differentiated and pluri- or totipotent cell states, whose fates are determined by interactions with combinations of unrelated transcription factors.

  • 15.
    Ganna, Andrea
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Broeckling, Corey D
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Magnusson, Patrik K E
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Pedersen, Nancy L
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Zilmer, Mihkel
    Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004801-Article in journal (Refereed)
    Abstract [en]

    Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.

  • 16.
    Giraud, Antoine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. INSERM, U571, Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, IFR94, Paris, France; NRA UEPSD, Jouy-en-Josas, France,.
    Arous, Safia
    De Paepe, Marianne
    Gaboriau-Routhiau, Valérie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Université Paris Descartes, Faculté de Médecine René Descartes, IFR94, Paris, France; INRA UEPSD, Jouy-en-Josas, France; INSERM, U793, Paris, France.
    Bambou, Jean-Christophe
    Rakotobe, Sabine
    Lindner, Ariel B.
    Taddei, Francois
    Cerf-Bensussan, Nadine
    Dissecting the genetic components of adaptation of Escherichia coli to the mouse gut2008In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 4, no 1, article id e2Article in journal (Refereed)
    Abstract [en]

    While pleiotropic adaptive mutations are thought to be central for evolution, little is known on the downstream molecular effects allowing adaptation to complex ecologically relevant environments. Here we show that Escherichia coli MG1655 adapts rapidly to the intestine of germ-free mice by single point mutations in EnvZ/OmpR two-component signal transduction system, which controls more than 100 genes. The selective advantage conferred by the mutations that modulate EnvZ/OmpR activities was the result of their independent and additive effects on flagellin expression and permeability. These results obtained in vivo thus suggest that global regulators may have evolved to coordinate activities that need to be fine-tuned simultaneously during adaptation to complex environments and that mutations in such regulators permit adjustment of the boundaries of physiological adaptation when switching between two very distinct environments.

  • 17.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Toft, Christina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaremba-Niedzwiedzka, Katarzyna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Gene Transfer Agent and a Dynamic Repertoire of Secretion Systems Hold the Keys to the Explosive Radiation of the Emerging Pathogen Bartonella2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3, p. e1003393-Article in journal (Refereed)
    Abstract [en]

    Gene transfer agents (GTAs) randomly transfer short fragments of a bacterial genome. A novel putative GTA was recently discovered in the mouse-infecting bacterium Bartonella grahamii. Although GTAs are widespread in phylogenetically diverse bacteria, their role in evolution is largely unknown. Here, we present a comparative analysis of 16 Bartonella genomes ranging from 1.4 to 2.6 Mb in size, including six novel genomes from Bartonella isolated from a cow, two moose, two dogs, and a kangaroo. A phylogenetic tree inferred from 428 orthologous core genes indicates that the deadly human pathogen B. bacilliformis is related to the ruminant-adapted clade, rather than being the earliest diverging species in the genus as previously thought. A gene flux analysis identified 12 genes for a GTA and a phage-derived origin of replication as the most conserved innovations. These are located in a region of a few hundred kb that also contains 8 insertions of gene clusters for type III, IV, and V secretion systems, and genes for putatively secreted molecules such as cholera-like toxins. The phylogenies indicate a recent transfer of seven genes in the virB gene cluster for a type IV secretion system from a catadapted B. henselae to a dog-adapted B. vinsonii strain. We show that the B. henselae GTA is functional and can transfer genes in vitro. We suggest that the maintenance of the GTA is driven by selection to increase the likelihood of horizontal gene transfer and argue that this process is beneficial at the population level, by facilitating adaptive evolution of the host-adaptation systems and thereby expansion of the host range size. The process counters gene loss and forces all cells to contribute to the production of the GTA and the secreted molecules. The results advance our understanding of the role that GTAs play for the evolution of bacterial genomes.

  • 18.
    Hollfelder, Nina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Schlebusch, Carina M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Günther, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Babiker, Hiba
    Dept. of Linguistic and Cultural Evolution, Max Planck Institute for the Science of Human History, Jena, Germany..
    Hassan, Hisham Y.
    Banoon ART and Cytogenetics Centre, Bahrain Defense Force Hospital, Manama, Kingdom of Bahrain..
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Northeast African genomic variation shaped by the continuity of indigenous groups and Eurasian migrations2017In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 8, article id e1006976Article in journal (Refereed)
    Abstract [en]

    Northeast Africa has a long history of human habitation, with fossil-finds from the earliest anatomically modern humans, and housing ancient civilizations. The region is also the gateway out of Africa, as well as a portal for migration into Africa from Eurasia via the Middle East and the Arabian Peninsula. We investigate the population history of northeast Africa by genotyping similar to 3.9 million SNPs in 221 individuals from 18 populations sampled in Sudan and South Sudan and combine this data with published genome-wide data from surrounding areas. We find a strong genetic divide between the populations from the northeastern parts of the region (Nubians, central Arab populations, and the Beja) and populations towards the west and south (Nilotes, Darfur and Kordofan populations). This differentiation is mainly caused by a large Eurasian ancestry component of the northeast populations likely driven by migration of Middle Eastern groups followed by admixture that affected the local populations in a north-to-south succession of events. Genetic evidence points to an early admixture event in the Nubians, concurrent with historical contact between North Sudanese and Arab groups. We estimate the admixture in current-day Sudanese Arab populations to about 700 years ago, coinciding with the fall of Dongola in 1315/1316 AD, a wave of admixture that reached the Darfurian/Kordofanian populations some 400-200 years ago. In contrast to the northeastern populations, the current-day Nilotic populations from the south of the region display little or no admixture from Eurasian groups indicating long-term isolation and population continuity in these areas of northeast Africa.

  • 19.
    Horikoshi, Momoko
    et al.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    van de Bunt, Martijn
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Surakka, Ida
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Sarin, Antti-Pekka
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Marullo, Letizia
    Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy..
    Thorleifsson, Gudmar
    deCode Genet Amgen Inc, Reykjavik, Iceland..
    Hägg, Sara
    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 Epidemiol & Biostatist, Stockholm, Sweden..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Ladenvall, Claes
    Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Ried, Janina S.
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany..
    Willems, Sara M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Beekman, Marian
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Expt Gen, Lubeck, Germany.;DZHK German Ctr Cardiovascular Res, Lubeck, Germany..
    Wiltshire, Steven
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Fernandez, Juan
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Steinthorsdottir, Valgerdur
    deCode Genet Amgen Inc, Reykjavik, Iceland..
    Hamsten, Anders
    Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Cardiovascular Genet & Genom Grp, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    Robertson, Neil R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Groves, Christopher J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Bennett, Amanda J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Lehtimaeki, Terho
    Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland.;Univ Tampere, Sch Med, FIN-33101 Tampere, Finland..
    Viikari, Jorma S.
    Univ Turku, Dept Med, Turku, Finland.;Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland..
    Rung, Johan
    European Bioinformat Inst, European Mol Biol Lab, Hinxton, England..
    Lyssenko, Valeriya
    Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Steno Diabet Ctr AS, Gentofte, Denmark..
    Perola, Markus
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Heid, Iris M.
    Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany..
    Herder, Christian
    Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany..
    Grallert, Harald
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;Univ Munich, Inst Med Informat,Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany..
    Roden, Michael
    Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany.;Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Hypponen, Elina
    Univ S Australia, Sch Populat Hlth, Adelaide, SA 5001, Australia.;UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England..
    Isaacs, Aaron
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    van Leeuwen, Elisabeth M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Karssen, Lennart C.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Houwing-Duistermaat, Jeanine J.
    Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands..
    de Craen, Anton J. M.
    Netherlands Consortium Hlth Ageing, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Deelen, Joris
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Havulinna, Aki S.
    Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland..
    Blades, Matthew
    Univ Leicester, Bioinformat & Biostatist Support Hub, Leicester, Leics, England..
    Hengstenberg, Christian
    Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Gen, Lubeck, Germany.;DZHK German Ctr Cardiovascular Res, Lubeck, Germany..
    Schunkert, Heribert
    Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Kaprio, Jaakko
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Tobin, Martin D.
    Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Resp Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst Harvard & MIT, Broad Inst, Cambridge, MA USA..
    Slagboom, P. Eline
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    van Duijn, Cornelia M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Vasa Cent Hosp, Vaasa, Finland.;Natl Inst Hlth & Welf, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland..
    Peters, Annette
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Gieger, Christian
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Turku, Finland..
    Groop, Leif
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Raitakari, Olli T.
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.;Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland.;Turku Univ Hosp, FIN-20520 Turku, Finland..
    Power, Chris
    UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    de Geus, Eco
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Smit, Johannes H.
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    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. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Thorsteinsdottir, Unnur
    deCode Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stefansson, Kari
    deCode Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland.;Wellcome Trust Sanger Inst, Cambridge, England..
    Prokopenko, Inga
    Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, Sch Publ Hlth, London, England..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England.;Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 7, article id e1005230Article in journal (Refereed)
    Abstract [en]

    Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

  • 20. Jagannathan, Vidhya
    et al.
    Bannoehr, Jeanette
    Plattet, Philippe
    Hauswirth, Regula
    Droegemueller, Cord
    Droegemueller, Michaela
    Wiener, Dominique J.
    Doherr, Marcus
    Owczarek-Lipska, Marta
    Galichet, Arnaud
    Welle, Monika M.
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergvall, Kerstin
    Lohi, Hannes
    Ruefenacht, Silvia
    Linek, Monika
    Paradis, Manon
    Mueller, Eliane J.
    Roosje, Petra
    Leeb, Tosso
    A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 10, p. e1003848-Article in journal (Refereed)
    Abstract [en]

    Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4x10(-14)). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38x coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.

  • 21. Johnsson, Martin
    et al.
    Gustafson, Ida
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sahlqvist, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Wright, Dominic
    A Sexual Ornament in Chickens Is Affected by Pleiotropic Alleles at HAO1 and BMP2, Selected during Domestication2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 8, p. e1002914-Article in journal (Refereed)
    Abstract [en]

    Domestication is one of the strongest forms of short-term, directional selection. Although selection is typically only exerted on one or a few target traits, domestication can lead to numerous changes in many seemingly unrelated phenotypes. It is unknown whether such correlated responses are due to pleiotropy or linkage between separate genetic architectures. Using three separate intercrosses between wild and domestic chickens, a locus affecting comb mass (a sexual ornament in the chicken) and several fitness traits (primarily medullary bone allocation and fecundity) was identified. This locus contains two tightly-linked genes, BMP2 and HAO1, which together produce the range of pleiotropic effects seen. This study demonstrates the importance of pleiotropy (or extremely close linkage) in domestication. The nature of this pleiotropy also provides insights into how this sexual ornament could be maintained in wild populations.

  • 22. Johnsson, Martin
    et al.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Wright, Dominic
    Genetic Regulation of Bone Metabolism in the Chicken: Similarities and Differences to Mammalian Systems2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 5, article id e1005250Article in journal (Refereed)
    Abstract [en]

    Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.

  • 23. Lauc, Gordan
    et al.
    Huffman, Jennifer E.
    Pucic, Maja
    Zgaga, Lina
    Adamczyk, Barbara
    Muzinic, Ana
    Novokmet, Mislav
    Polasek, Ozren
    Gornik, Olga
    Kristic, Jasminka
    Keser, Toma
    Vitart, Veronique
    Scheijen, Blanca
    Uh, Hae-Won
    Molokhia, Mariam
    Patrick, Alan Leslie
    McKeigue, Paul
    Kolcic, Ivana
    Lukic, Ivan Kresimir
    Swann, Olivia
    van Leeuwen, Frank N.
    Ruhaak, L. Renee
    Houwing-Duistermaat, Jeanine J.
    Slagboom, P. Eline
    Beekman, Marian
    de Craen, Anton J. M.
    Deelder, Andre M.
    Zeng, Qiang
    Wang, Wei
    Hastie, Nicholas D.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilson, James F.
    Wuhrer, Manfred
    Wright, Alan F.
    Rudd, Pauline M.
    Hayward, Caroline
    Aulchenko, Yurii
    Campbell, Harry
    Rudan, Igor
    Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 1, p. e1003225-Article in journal (Refereed)
    Abstract [en]

    Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27x10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e. g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve=0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.

  • 24. Mahajan, Anubha
    et al.
    Sim, Xueling
    Ng, Hui Jin
    Manning, Alisa
    Rivas, Manuel A
    Highland, Heather M
    Locke, Adam E
    Grarup, Niels
    Im, Hae Kyung
    Cingolani, Pablo
    Flannick, Jason
    Fontanillas, Pierre
    Fuchsberger, Christian
    Gaulton, Kyle J
    Teslovich, Tanya M
    Rayner, N William
    Robertson, Neil R
    Beer, Nicola L
    Rundle, Jana K
    Bork-Jensen, Jette
    Ladenvall, Claes
    Blancher, Christine
    Buck, David
    Buck, Gemma
    Burtt, Noël P
    Gabriel, Stacey
    Gjesing, Anette P
    Groves, Christopher J
    Hollensted, Mette
    Huyghe, Jeroen R
    Jackson, Anne U
    Jun, Goo
    Justesen, Johanne Marie
    Mangino, Massimo
    Murphy, Jacquelyn
    Neville, Matt
    Onofrio, Robert
    Small, Kerrin S
    Stringham, Heather M
    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.
    Trakalo, Joseph
    Abecasis, Goncalo
    Bell, Graeme I
    Blangero, John
    Cox, Nancy J
    Duggirala, Ravindranath
    Hanis, Craig L
    Seielstad, Mark
    Wilson, James G
    Christensen, Cramer
    Brandslund, Ivan
    Rauramaa, Rainer
    Surdulescu, Gabriela L
    Doney, Alex S F
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Linneberg, Allan
    Isomaa, Bo
    Tuomi, Tiinamaija
    Jørgensen, Marit E
    Jørgensen, Torben
    Kuusisto, Johanna
    Uusitupa, Matti
    Salomaa, Veikko
    Spector, Timothy D
    Morris, Andrew D
    Palmer, Colin N A
    Collins, Francis S
    Mohlke, Karen L
    Bergman, Richard N
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Tuomilehto, Jaakko
    Hansen, Torben
    Watanabe, Richard M
    Prokopenko, Inga
    Dupuis, Josee
    Karpe, Fredrik
    Groop, Leif
    Laakso, Markku
    Pedersen, Oluf
    Florez, Jose C
    Morris, Andrew P
    Altshuler, David
    Meigs, James B
    Boehnke, Michael
    McCarthy, Mark I
    Lindgren, Cecilia M
    Gloyn, Anna L
    Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 1, article id e1004876Article in journal (Refereed)
    Abstract [en]

    Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

  • 25. McCue, Molly E.
    et al.
    Bannasch, Danika L.
    Petersen, Jessica L.
    Gurr, Jessica
    Bailey, Ernie
    Binns, Matthew M.
    Distl, Ottmar
    Guerin, Gerard
    Hasegawa, Telhisa
    Hill, Emmeline W.
    Leeb, Tosso
    Lindgren, Gabriella
    Penedo, M. Cecilia T.
    Roed, Knut H.
    Ryder, Oliver A.
    Swinburne, June E.
    Tozaki, Teruaki
    Valberg, Stephanie J.
    Vaudin, Mark
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wade, Claire M.
    Mickelson, James R.
    A High Density SNP Array for the Domestic Horse and Extant Perissodactyla: Utility for Association Mapping, Genetic Diversity, and Phylogeny Studies2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 1, p. e1002451-Article in journal (Refereed)
    Abstract [en]

    An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of similar to 43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50-100 kb and reached background levels within 1-2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the Mongolian and Quarter Horse. Multidimensional scaling (MDS) analyses demonstrated the tight grouping of individuals within most breeds, close proximity of related breeds, and less tight grouping in admixed breeds. The close relationship between the Przewalski's Horse and the domestic horse was demonstrated by pair-wise genetic distance and MDS. Genotyping of other Perissodactyla (zebras, asses, tapirs, and rhinoceros) was variably successful, with call rates and the number of polymorphic loci varying across taxa. Parsimony analysis placed the modern horse as sister taxa to Equus przewalski. The utility of the SNP array in genome-wide association was confirmed by mapping the known recessive chestnut coat color locus (MC1R) and defining a conserved haplotype of similar to 750 kb across all breeds. These results demonstrate the high quality of this SNP genotyping resource, its usefulness in diverse genome analyses of the horse, and potential use in related species.

  • 26.
    Nadachowska-Brzyska, Krystyna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Burri, Reto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Olason, Pall
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Kawakami, Takeshi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Smeds, Linnéa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Demographic Divergence History of Pied Flycatcher and Collared Flycatcher Inferred from Whole-Genome Re-sequencing Data2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 11, p. e1003942-Article in journal (Refereed)
    Abstract [en]

    Profound knowledge of demographic history is a prerequisite for the understanding and inference of processes involved in the evolution of population differentiation and speciation. Together with new coalescent-based methods, the recent availability of genome-wide data enables investigation of differentiation and divergence processes at unprecedented depth. We combined two powerful approaches, full Approximate Bayesian Computation analysis (ABC) and pairwise sequentially Markovian coalescent modeling (PSMC), to reconstruct the demographic history of the split between two avian speciation model species, the pied flycatcher and collared flycatcher. Using whole-genome re-sequencing data from 20 individuals, we investigated 15 demographic models including different levels and patterns of gene flow, and changes in effective population size over time. ABC provided high support for recent (mode 0.3 my, range <0.7 my) species divergence, declines in effective population size of both species since their initial divergence, and unidirectional recent gene flow from pied flycatcher into collared flycatcher. The estimated divergence time and population size changes, supported by PSMC results, suggest that the ancestral species persisted through one of the glacial periods of middle Pleistocene and then split into two large populations that first increased in size before going through severe bottlenecks and expanding into their current ranges. Secondary contact appears to have been established after the last glacial maximum. The severity of the bottlenecks at the last glacial maximum is indicated by the discrepancy between current effective population sizes (20,000–80,000) and census sizes (5–50 million birds) of the two species. The recent divergence time challenges the supposition that avian speciation is a relatively slow process with extended times for intrinsic postzygotic reproductive barriers to evolve. Our study emphasizes the importance of using genome-wide data to unravel tangled demographic histories. Moreover, it constitutes one of the first examples of the inference of divergence history from genome-wide data in non-model species.

  • 27. O'Seaghdha, Conall M.
    et al.
    Wu, Hongsheng
    Yang, Qiong
    Kapur, Karen
    Guessous, Idris
    Zuber, Annie Mercier
    Koettgen, Anna
    Stoudmann, Candice
    Teumer, Alexander
    Kutalik, Zoltan
    Mangino, Massimo
    Dehghan, Abbas
    Zhang, Weihua
    Eiriksdottir, Gudny
    Li, Guo
    Tanaka, Toshiko
    Portas, Laura
    Lopez, Lorna M.
    Hayward, Caroline
    Lohman, Kurt
    Matsuda, Koichi
    Padmanabhan, Sandosh
    Firsov, Dmitri
    Sorice, Rossella
    Ulivi, Sheila
    Brockhaus, A. Catharina
    Kleber, Marcus E.
    Mahajan, Anubha
    Ernst, Florian D.
    Gudnason, Vilmundur
    Launer, Lenore J.
    Mace, Aurelien
    Boerwinckle, Eric
    Arking, Dan E.
    Tanikawa, Chizu
    Nakamura, Yusuke
    Brown, Morris J.
    Gaspoz, Jean-Michel
    Theler, Jean-Marc
    Siscovick, David S.
    Psaty, Bruce M.
    Bergmann, Sven
    Vollenweider, Peter
    Vitart, Veronique
    Wright, Alan F.
    Zemunik, Tatijana
    Boban, Mladen
    Kolcic, Ivana
    Navarro, Pau
    Brown, Edward M.
    Estrada, Karol
    Ding, Jingzhong
    Harris, Tamara B.
    Bandinelli, Stefania
    Hernandez, Dena
    Singleton, Andrew B.
    Girotto, Giorgia
    Ruggiero, Daniela
    d'Adamo, Adamo Pio
    Robino, Antonietta
    Meitinger, Thomas
    Meisinger, Christa
    Davies, Gail
    Starr, John M.
    Chambers, John C.
    Boehm, Bernhard O.
    Winkelmann, Bernhard R.
    Huang, Jie
    Murgia, Federico
    Wild, Sarah H.
    Campbell, Harry
    Morris, Andrew P.
    Franco, Oscar H.
    Hofman, Albert
    Uitterlinden, Andre G.
    Rivadeneira, Fernando
    Voelker, Uwe
    Hannemann, Anke
    Biffar, Reiner
    Hoffmann, Wolfgang
    Shin, So-Youn
    Lescuyer, Pierre
    Henry, Hughes
    Schurmann, Claudia
    Munroe, Patricia B.
    Gasparini, Paolo
    Pirastu, Nicola
    Ciullo, Marina
    Gieger, Christian
    Maerz, Winfried
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Spector, Tim D.
    Smith, Albert V.
    Rudan, Igor
    Wilson, James F.
    Polasek, Ozren
    Deary, Ian J.
    Pirastu, Mario
    Ferrucci, Luigi
    Liu, Yongmei
    Kestenbaum, Bryan
    Kooner, Jaspal S.
    Witteman, Jacqueline C. M.
    Nauck, Matthias
    Kao, W. H. Linda
    Wallaschofski, Henri
    Bonny, Olivier
    Fox, Caroline S.
    Bochud, Murielle
    Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 9, p. e1003796-Article in journal (Refereed)
    Abstract [en]

    Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

  • 28. Paternoster, Lavinia
    et al.
    Lorentzon, Mattias
    Lehtimaki, Terho
    Eriksson, Joel
    Kahonen, Mika
    Raitakari, Olli
    Laaksonen, Marika
    Sievanen, Harri
    Viikari, Jorma
    Lyytikainen, Leo-Pekka
    Mellstrom, Dan
    Karlsson, Magnus
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Grundberg, Elin
    Kemp, John P.
    Sayers, Adrian
    Nethander, Maria
    Evans, David M.
    Vandenput, Liesbeth
    Tobias, Jon H.
    Ohlsson, Claes
    Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 2, p. e1003247-Article in journal (Refereed)
    Abstract [en]

    Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6x10(-14); LOC285735, rs271170, p = 2.7x10(-12); OPG, rs7839059, p = 1.2x10(-10); and ESR1/C6orf97, rs6909279, p = 1.1x10(-9)). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9x10(-9)). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

  • 29. Randall, Joshua C.
    et al.
    Winkler, Thomas W.
    Kutalik, Zoltan
    Berndt, Sonja I.
    Jackson, Anne U.
    Monda, Keri L.
    Kilpelaeinen, Tuomas O.
    Esko, Tonu
    Maegi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F.
    Croteau-Chonka, Damien C.
    Day, Felix R.
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E.
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R.
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T.
    Dimas, Antigone S.
    Karpe, Fredrik
    Min, Josine L.
    Nicholson, George
    Clegg, Deborah J.
    Person, Thomas
    Krohn, Jon P.
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amelie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L.
    Harris, Tamara B.
    Smith, Albert Vernon
    Shuldiner, Alan R.
    McArdle, Wendy L.
    Caulfield, Mark J.
    Munroe, Patricia B.
    Gronberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S.
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A.
    Kraja, Aldi T.
    Province, Michael A.
    Cupples, L. Adrienne
    Heard-Costa, Nancy L.
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S.
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H. Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Pramstaller, Peter P.
    Kathiresan, Sekar
    Speliotes, Elizabeth K.
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Boomsma, Dorret I.
    Campbell, Harry
    Wilson, James F.
    Chanock, Stephen J.
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, Andre G.
    Hofman, Albert
    Zillikens, M. Carola
    den Heijer, Martin
    Kiemeney, Lambertus A.
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Voelzke, Henry
    Kovacs, Peter
    Toenjes, Anke
    Mangino, Massimo
    Spector, Tim D.
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S.
    Samani, Nilesh J.
    Attwood, Antony Paul
    Sambrook, Jennifer G.
    Hung, Joseph
    Palmer, Lyle J.
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G.
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M.
    Snieder, Harold
    Van der Klauw, Melanie M.
    Van Vliet-Ostaptchouk, Jana V.
    Gejman, Pablo V.
    Shi, Jianxin
    Jacobs, Kevin B.
    Wang, Zhaoming
    Bakker, Stephan J. L.
    Leach, Irene Mateo
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G.
    Medland, Sarah E.
    Montgomery, Grant W.
    Yang, Jian
    Chasman, Daniel I.
    Ridker, Paul M.
    Rose, Lynda M.
    Lehtimaki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G.
    Hyppoenen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P.
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R.
    Schwarz, Peter E. H.
    Kristiansson, Kati
    Perola, Markus
    Lindstrom, Jaana
    Swift, Amy J.
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A.
    Rauramaa, Rainer
    Bolton, Jennifer L.
    Fowkes, Gerry
    Fraser, Ross M.
    Price, Jackie F.
    Fischer, Krista
    KrjutAikov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K.
    Chines, Peter S.
    Keinanen-Kiukaanniemi, Sirkka M.
    Saaristo, Timo E.
    Edkins, Sarah
    Franks, Paul W.
    Hallmans, Goran
    Shungin, Dmitry
    Morris, Andrew David
    Palmer, Colin N. A.
    Erbel, Raimund
    Moebus, Susanne
    Noethen, Markus M.
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E.
    Strawbridge, Rona J.
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Mueller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O.
    Kleber, Marcus E.
    Maerz, Winfried
    Winkelmann, Bernhard R.
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W. G.
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L.
    Njolstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L.
    Barroso, Ine S.
    Boehnke, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Frayling, Timothy
    Groop, Leif C.
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L.
    O'Connell, Jeffrey R.
    Schlessinger, David
    Strachan, David P.
    Stefansson, Kari
    van Duijn, Cornelia M.
    Abecasis, Goncalo R.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Qi, Lu
    Loos, Ruth J. F.
    Lindgren, Cecilia M.
    North, Kari E.
    Heid, Iris M.
    Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 6, p. e1003500-Article in journal (Refereed)
    Abstract [en]

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5x10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  • 30.
    Stocks, Michael
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Dean, Rebecca
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Rogell, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Friberg, Urban
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Sex-specific Trans-regulatory Variation on the Drosophila melanogaster X Chromosome2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, article id e1005015Article in journal (Refereed)
    Abstract [en]

    The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.

  • 31.
    Suh, Alexander Sang-Jae
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Weber, Claudia C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Kehlmaier, Christian
    Braun, Edward L.
    Green, Richard E.
    Fritz, Uwe
    Ray, David A.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Early Mesozoic Coexistence of Amniotes and Hepadnaviridae2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004559-Article in journal (Refereed)
    Abstract [en]

    Hepadnaviridae are double-stranded DNA viruses that infect some species of birds and mammals. This includes humans, where hepatitis B viruses (HBVs) are prevalent pathogens in considerable parts of the global population. Recently, endogenized sequences of HBVs (eHBVs) have been discovered in bird genomes where they constitute direct evidence for the coexistence of these viruses and their hosts from the late Mesozoic until present. Nevertheless, virtually nothing is known about the ancient host range of this virus family in other animals. Here we report the first eHBVs from crocodilian, snake, and turtle genomes, including a turtle eHBV that endogenized >207 million years ago. This genomic "fossil'' is >125 million years older than the oldest avian eHBV and provides the first direct evidence that Hepadnaviridae already existed during the Early Mesozoic. This implies that the Mesozoic fossil record of HBV infection spans three of the five major groups of land vertebrates, namely birds, crocodilians, and turtles. We show that the deep phylogenetic relationships of HBVs are largely congruent with the deep phylogeny of their amniote hosts, which suggests an ancient amniote-HBV coexistence and codivergence, at least since the Early Mesozoic. Notably, the organization of overlapping genes as well as the structure of elements involved in viral replication has remained highly conserved among HBVs along that time span, except for the presence of the X gene. We provide multiple lines of evidence that the tumor-promoting X protein of mammalian HBVs lacks a homolog in all other hepadnaviruses and propose a novel scenario for the emergence of X via segmental duplication and overprinting of pre-existing reading frames in the ancestor of mammalian HBVs. Our study reveals an unforeseen host range of prehistoric HBVs and provides novel insights into the genome evolution of hepadnaviruses throughout their long-lasting association with amniote hosts.

  • 32.
    Sun, Yu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Corcoran, Padraic
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Menkis, Audrius
    Whittle, Carrie A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Johannesson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Large-Scale Introgression Shapes the Evolution of the Mating-Type Chromosomes of the Filamentous Ascomycete Neurospora tetrasperma2012In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 7, p. e1002820-Article in journal (Refereed)
    Abstract [en]

    The significance of introgression as an evolutionary force shaping natural populations is well established, especially in animal and plant systems. However, the abundance and size of introgression tracts, and to what degree interspecific gene flow is the result of adaptive processes, are largely unknown. In this study, we present medium coverage genomic data from species of the filamentous ascomycete Neurospora, and we use comparative genomics to investigate the introgression landscape at the genomic level in this model genus. We revealed one large introgression tract in each of the three investigated phylogenetic lineages of Neurospora tetrasperma (sizes of 5.6 Mbp, 5.2 Mbp, and 4.1 Mbp, respectively). The tract is located on the chromosome containing the locus conferring sexual identity, the mating-type (mat) chromosome. The region of introgression is confined to the region of suppressed recombination and is found on one of the two mat chromosomes (mat a). We used Bayesian concordance analyses to exclude incomplete lineage sorting as the cause for the observed pattern, and multilocus genealogies from additional species of Neurospora show that the introgression likely originates from two closely related, freely recombining, heterothallic species (N. hispaniola and N. crassa/N. perkinsii). Finally, we investigated patterns of molecular evolution of the mat chromosome in Neurospora, and we show that introgression is correlated with reduced level of molecular degeneration, consistent with a shorter time of recombination suppression. The chromosome specific (mat) and allele specific (mat a) introgression reported herein comprise the largest introgression tracts reported to date from natural populations. Furthermore, our data contradicts theoretical predictions that introgression should be less likely on sex-determining chromosomes. Taken together, the data presented herein advance our general understanding of introgression as a force shaping eukaryotic genomes.

  • 33.
    Tengvall, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kierczak, Marcin
    Bergvall, Kerstin
    Olsson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frankowiack, Marcel
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Leeb, Tosso
    Andersson, Göran
    Hammarström, Lennart
    Hedhammar, Åke
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
    Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, p. e1003475-Article in journal (Refereed)
    Abstract [en]

    Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

  • 34. Thun, Gian Andri
    et al.
    Imboden, Medea
    Ferrarotti, Ilaria
    Kumar, Ashish
    Obeidat, Ma'en
    Zorzetto, Michele
    Haun, Margot
    Curjuric, Ivan
    Alves, Alexessander Couto
    Jackson, Victoria E.
    Albrecht, Eva
    Ried, Janina S.
    Teumer, Alexander
    Lopez, Lorna M.
    Huffman, Jennifer E.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bosse, Yohan
    Hao, Ke
    Timens, Wim
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Polasek, Ozren
    Wilson, James F.
    Rudan, Igor
    Hayward, Caroline
    Sandford, Andrew J.
    Deary, Ian J.
    Koch, Beate
    Reischl, Eva
    Schulz, Holger
    Hui, Jennie
    James, Alan L.
    Rochat, Thierry
    Russi, Erich W.
    Jarvelin, Marjo-Riitta
    Strachan, David P.
    Hall, Ian P.
    Tobin, Martin D.
    Dahl, Morten
    Nielsen, Sune Fallgaard
    Nordestgaard, Borge G.
    Kronenberg, Florian
    Luisetti, Maurizio
    Probst-Hensch, Nicole M.
    Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 8, p. e1003585-Article in journal (Refereed)
    Abstract [en]

    Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs defined by showing minor allele frequencies (MAFs) >5% reached genome-wide significance all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of beta = 20.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis as well as exon-sequencing in a subsample (N = 410) suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only in particular by the well-documented protein inhibitor S and Z (PI S PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001) as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397) associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

  • 35. Tonomura, Noriko
    et al.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thomas, Rachael
    Megquier, Kate
    Turner-Maier, Jason
    Howald, Cedric
    Sarver, Aaron L.
    Swofford, Ross
    Frantz, Aric M.
    Ito, Daisuke
    Mauceli, Evan
    Arendt, Maja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Noh, Hyun Ji
    Koltookian, Michele
    Biagi, Tara
    Fryc, Sarah
    Williams, Christina
    Avery, Anne C.
    Kim, Jong-Hyuk
    Barber, Lisa
    Burgess, Kristine
    Lander, Eric S.
    Karlsson, Elinor K.
    Azuma, Chieko
    Modiano, Jaime F.
    Breen, Matthew
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 2, article id e1004922Article in journal (Refereed)
    Abstract [en]

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute similar to 20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6x10(-7) and 2.7x10(-6), respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangio-sarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.

  • 36.
    Wallberg, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glemin, Sylvain
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Extreme Recombination Frequencies Shape Genome Variation and Evolution in the Honeybee, Apis mellifera2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 4, article id e1005189Article in journal (Refereed)
    Abstract [en]

    Meiotic recombination is a fundamental cellular process, with important consequences for evolution and genome integrity. However, we know little about how recombination rates vary across the genomes of most species and the molecular and evolutionary determinants of this variation. The honeybee, Apis mellifera, has extremely high rates of meiotic recombination, although the evolutionary causes and consequences of this are unclear. Here we use patterns of linkage disequilibrium in whole genome resequencing data from 30 diploid honeybees to construct a fine-scale map of rates of crossing over in the genome. We find that, in contrast to vertebrate genomes, the recombination landscape is not strongly punctate. Crossover rates strongly correlate with levels of genetic variation, but not divergence, which indicates a pervasive impact of selection on the genome. Germ-line methylated genes have reduced crossover rate, which could indicate a role of methylation in suppressing recombination. Controlling for the effects of methylation, we do not infer a strong association between gene expression patterns and recombination. The site frequency spectrum is strongly skewed from neutral expectations in honeybees: rare variants are dominated by AT-biased mutations, whereas GC-biased mutations are found at higher frequencies, indicative of a major influence of GC-biased gene conversion (gBGC), which we infer to generate an allele fixation bias 5 - 50 times the genomic average estimated in humans. We uncover further evidence that this repair bias specifically affects transitions and favours fixation of CpG sites. Recombination, via gBGC, therefore appears to have profound consequences on genome evolution in honeybees and interferes with the process of natural selection. These findings have important implications for our understanding of the forces driving molecular evolution.

  • 37.
    Watthanasurorot, Apiruck
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Saelee, Netnapa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Phongdara, Amornrat
    Roytrakul, Sittiruk
    Jiravanichpaisal, Pikul
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Kenneth
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Söderhäll, Irene
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Astakine 2-the Dark Knight Linking Melatonin to Circadian Regulation in Crustaceans2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3, p. e1003361-Article in journal (Refereed)
    Abstract [en]

    Daily, circadian rhythms influence essentially all living organisms and affect many physiological processes from sleep and nutrition to immunity. This ability to respond to environmental daily rhythms has been conserved along evolution, and it is found among species from bacteria to mammals. The hematopoietic process of the crayfish Pacifastacus leniusculus is under circadian control and is tightly regulated by astakines, a new family of cytokines sharing a prokineticin (PROK) domain. The expression of AST1 and AST2 are light-dependent, and this suggests an evolutionarily conserved function for PROK domain proteins in mediating circadian rhythms. Vertebrate PROKs are transmitters of circadian rhythms of the suprachiasmatic nucleus (SCN) in the brain of mammals, but the mechanism by which they function is unknown. Here we demonstrate that high AST2 expression is induced by melatonin in the brain. We identify RACK1 as a binding protein of AST2 and further provide evidence that a complex between AST2 and RACK1 functions as a negative-feedback regulator of the circadian clock. By DNA mobility shift assay, we showed that the AST2-RACK1 complex will interfere with the binding between BMAL1 and CLK and inhibit the E-box binding activity of the complex BMAL1-CLK. Finally, we demonstrate by gene knockdown that AST2 is necessary for melatonin-induced inhibition of the complex formation between BMAL1 and CLK during the dark period. In summary, we provide evidence that melatonin regulates AST2 expression and thereby affects the core clock of the crustacean brain. This process may be very important in all animals that have AST2 molecules, i.e. spiders, ticks, crustaceans, scorpions, several insect groups such as Hymenoptera, Hemiptera, and Blattodea, but not Diptera and Coleoptera. Our findings further reveal an ancient evolutionary role for the prokineticin superfamily protein that links melatonin to direct regulation of the core clock gene feedback loops.

  • 38. Wilbe, Maria
    et al.
    Kozyrev, Sergey V.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Farias, Fabiana H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bremer, Hanna D.
    Hedlund, Anna
    Pielberg, Gerli R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Seppala, Eija H.
    Gustafson, Ulla
    Lohi, Hannes
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Andersson, Goran
    Hansson-Hamlin, Helene
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 6, article id e1005248Article in journal (Refereed)
    Abstract [en]

    The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAM-TOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

  • 39.
    Williams, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dnyansagar, Rohit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kasagiannis, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Akram, Mehwish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kheder, Sania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Ambrosi, Valerie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hallqvist, Emilie
    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.
    Schiöth, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The Drosophila ETV5 homologue Ets96B: Molecular link between obesity and bipolar disorder2016In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 6, article id e1006104Article in journal (Refereed)
    Abstract [en]

    Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. For instance, obese individuals are more impulsive and have heightened reward responsiveness, phenotypes associated with BD, while bipolar patients become obese at a higher rate and earlier age than people without BD; however, the molecular mechanisms of such an association remain obscure. Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. We identify a novel molecular link between obesity and bipolar disorder. The Drosophila ETV5 homologue Ets96B regulates the expression of cellular systems with links to obesity and behaviour, including the expression of a conserved endoplasmic reticulum molecular chaperone complex known to be neuroprotective. Finally, a connection between the obesity- linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level.

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