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  • 1.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Johansson, Åsa
    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.
    Zaboli, Ghazal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Igl, Wilmar
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Anna C. V.
    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.
    Rivas, Manuel A.
    Daly, Mark J.
    Schmitz, Gerd
    Hicks, Andrew A.
    Meitinger, Thomas
    Feuk, Lars
    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.
    van Duijn, Cornelia
    Oostra, Ben
    Pramstaller, Peter P.
    Rudan, Igor
    Wright, Alan F.
    Wilson, James F.
    Campbell, Harry
    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.
    Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 5, p. 809-820Article in journal (Refereed)
    Abstract [en]

    Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.

  • 2.
    Bakalkin, Georgy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jezierska, Justyna
    Depoorter, Cloë
    Verschuuren-Bemelmans, Corien
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Artemenko, Konstantin A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Yakovleva, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dooijes, Dennis
    Van de Warrenburg, Bart P. C.
    Zubarev, Roman A.
    Kremer, Berry
    Knapp, Pamela E.
    Hauser, Kurt F.
    Wijmenga, Cisca
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sinke, Richard J.
    Verbeek, Dineke S.
    Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23.2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 87, no 5, p. 593-603Article in journal (Refereed)
    Abstract [en]

    Spinocerebellar ataxias (SCAs) are dominantly inherited neurodegenerative disorders characterized by progressive cerebellar ataxia and dysarthria. We have identified missense mutations in prodynorphin (PDYN) that cause SCA23 in four Dutch families displaying progressive gait and limb ataxia. PDYN is the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B (Dyn A and B). Dynorphins regulate pain processing and modulate the rewarding effects of addictive substances. Three mutations were located in Dyn A, a peptide with both opioid activities and nonopioid neurodegenerative actions. Two of these mutations resulted in excessive generation of Dyn A in a cellular model system. In addition, two of the mutant Dyn A peptides induced toxicity above that of wild-type Dyn A in cultured striatal neurons. The fourth mutation was located in the nonopioid PDYN domain and was associated with altered expression of components of the opioid and glutamate system, as evident from analysis of SCA23 autopsy tissue. Thus, alterations in Dyn A activities and/or impairment of secretory pathways by mutant PDYN may lead to glutamate neurotoxicity, which underlies Purkinje cell degeneration and ataxia. PDYN mutations are identified in a small subset of ataxia families, indicating that SCA23 is an infrequent SCA type (~0.5%) in the Netherlands and suggesting further genetic SCA heterogeneity.

  • 3.
    Balciuniene, Jorune
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borg, Erik
    Samuelsson, Eva
    Koisti, Markus J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jazin, Elena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family1998In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 63, no 3, p. 786-93Article in journal (Refereed)
    Abstract [en]

    We investigated a Swedish family with nonsyndromic progressive bilateral sensorineural hearing loss. Thirteen candidate loci for autosomal dominant nonsyndromic hearing loss were tested for linkage in this family. We found significant LOD scores (>3) for markers at candidate locus DFNA12 (11q22-q24) and suggestive LOD scores (>2) for markers at locus DFNA2 (1p32). Our results for markers on chromosome 11 narrowed down the candidate region for the DFNA12 locus. A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the notion that two genes segregated together with hearing impairment in the family. Severely affected family members had haplotypes linked to the disease allele on both chromosomes 1 and 11, whereas individuals with milder hearing loss had haplotypes linked to the disease allele on either chromosome 1 or chromosome 11. These observations suggest an additive effect of two genes, each gene resulting in a mild and sometimes undiagnosed phenotype, but both together resulting in a more severe phenotype.

  • 4. Barbieri, Chiara
    et al.
    Vicente, Mário
    Rocha, Jorge
    Mpoloka, Sununguko W
    Stoneking, Mark
    Pakendorf, Brigitte
    Ancient substructure in early mtDNA lineages of southern Africa.2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 92, no 2Article in journal (Refereed)
    Abstract [en]

    Among the deepest-rooting clades in the human mitochondrial DNA (mtDNA) phylogeny are the haplogroups defined as L0d and L0k, which are found primarily in southern Africa. These lineages are typically present at high frequency in the so-called Khoisan populations of hunter-gatherers and herders who speak non-Bantu languages, and the early divergence of these lineages led to the hypothesis of ancient genetic substructure in Africa. Here we update the phylogeny of the basal haplogroups L0d and L0k with 500 full mtDNA genome sequences from 45 southern African Khoisan and Bantu-speaking populations. We find previously unreported subhaplogroups and greatly extend the amount of variation and time-depth of most of the known subhaplogroups. Our major finding is the definition of two ancient sublineages of L0k (L0k1b and L0k2) that are present almost exclusively in Bantu-speaking populations from Zambia; the presence of such relic haplogroups in Bantu speakers is most probably due to contact with ancestral pre-Bantu populations that harbored different lineages than those found in extant Khoisan. We suggest that although these populations went extinct after the immigration of the Bantu-speaking populations, some traces of their haplogroup composition survived through incorporation into the gene pool of the immigrants. Our findings thus provide evidence for deep genetic substructure in southern Africa prior to the Bantu expansion that is not represented in extant Khoisan populations.

  • 5. Bjursell, Magnus K.
    et al.
    Blom, Henk J.
    Cayuela, Jordi Asin
    Engvall, Martin L.
    Lesko, Nicole
    Balasubramaniam, Shanti
    Brandberg, Goran
    Halldin, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Falkenberg, Maria
    Jakobs, Cornelis
    Smith, Desiree
    Struys, Eduard
    von Dobeln, Ulrika
    Gustafsson, Claes M.
    Lundeberg, Joakim
    Wedell, Anna
    Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 4, p. 507-515Article in journal (Refereed)
    Abstract [en]

    Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (Ado Met), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

  • 6. Bruder, Carl E G
    et al.
    Piotrowski, Arkadiusz
    Gijsbers, Antoinet A C J
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Erickson, Stephen
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    von Tell, Desiree
    Poplawski, Andrzej
    Crowley, Michael
    Crasto, Chiquito
    Partridge, E Christopher
    Tiwari, Hemant
    Allison, David B
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    van Ommen, Gert-Jan B
    Boomsma, Dorret I
    Pedersen, Nancy L
    den Dunnen, Johan T
    Wirdefeldt, Karin
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles2008In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 82, no 3, p. 763-71Article in journal (Refereed)
    Abstract [en]

    The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.

  • 7. Burwinkel, Barbara
    et al.
    Scott, John W.
    Bührer, Christoph
    van Landeghem, Frank K. H.
    Cox, Gerald F.
    Wilson, Callum J.
    Hardie, D. Grahame
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, no 6, p. 1034-1049Article in journal (Refereed)
  • 8. Campos-Xavier, Ana Belinda
    et al.
    Martinet, Danielle
    Bateman, John
    Belluoccio, Dan
    Rowley, Lynn
    Tan, Tiong Yang
    Baxová, Alica
    Gustavson, Karl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borochowitz, Zvi U
    Innes, A. Micheil
    Unger, Sheila
    Beckmann, Jacques S.
    Mittaz, Lauréane
    Ballhausen, Diana
    Superti-Furga, Andrea
    Savarirayan, Ravi
    Bonafé, Luisa
    Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia2009In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 84, no 6, p. 760-70Article in journal (Refereed)
    Abstract [en]

    Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.

  • 9.
    Chami, Nathalie
    et al.
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada..
    Chen, Ming-Huei
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Slater, Andrew J.
    GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, Res Triangle Pk, NC 27709 USA.;OmicSoft Corp, Cary, NC 27513 USA..
    Eicher, John D.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Evangelou, Evangelos
    Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina 45110, Greece..
    Tajuddin, Salman M.
    NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA..
    Love-Gregory, Latisha
    Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA..
    Kacprowski, Tim
    Ernst Moritz Arndt Univ Greifswald, Dept Funct Gen, Interfaculty Inst Genet & Funct Gen, Univ Med, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany..
    Schick, Ursula M.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA..
    Nomura, Akihiro
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa 9200942, Japan..
    Giri, Ayush
    Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA..
    Lessard, Samuel
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada..
    Brody, Jennifer A.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA..
    Pankratz, Nathan
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med Div Gen Internal Med icine, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Manichaikul, Ani
    Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA..
    Pazoki, Raha
    Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Hill, W. David
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Raffield, Laura M.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Burt, Amber
    Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA..
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med Div Gen Internal Med icine, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Becker, Lewis C.
    Johns Hopkins Univ Sch Med, Dept Med, Div Cardiol & Gen Internal Med, Baltimore, MD 21205 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA..
    O'Donoghue, Michelle L.
    Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, Boston, MA 02115 USA..
    Crosslin, David R.
    Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA..
    de Denus, Simon
    Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada.;Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada..
    Dube, Marie-Pierre
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England..
    Engstrom, Gunnar
    Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA..
    Floyd, James S.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA..
    Gao, He
    Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England..
    Greinacher, Andreas
    Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark..
    Harris, Tamara B.
    NIA, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA..
    Hayward, Caroline
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland.;Univ Tampere, Sch Med, Tampere 33014, Finland..
    Highland, Heather M.
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA..
    Hirschhorn, Joel N.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA..
    Hofman, Albert
    Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Irvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Dept Clin Physiol, Sch Med, Tampere 33014, Finland..
    Lange, Ethan
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA..
    Launer, Lenore J.
    NIA, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Li, Jin
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94305 USA..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Linneberg, Allan
    Capital Region Denmark, Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, DK-2100 Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark..
    Liu, Yongmei
    Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Mathias, Rasika A.
    Johns Hopkins Univ Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA.;Johns Hopkins Univ Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Melander, Olle
    Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Mononen, Nina
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Nalls, Mike A.
    NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA..
    Nickerson, Deborah A.
    Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA..
    Nikus, Kjell
    Univ Tampere, Sch Med, Tampere 33014, Finland.;Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland..
    O'Donnell, Chris J.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.;Boston Vet Adm VA Healthcare, Cardiol Sect, Boston, MA 02118 USA.;Boston Vet Adm VA Healthcare, Ctr Populat Gen, Boston, MA 02118 USA..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark..
    Petersmann, Astrid
    Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany..
    Polfus, Linda
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland..
    Raitoharju, Emma
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Richard, Melissa
    Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rivadeneira, Fernando
    Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands.;Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;NCHA, NL-3015 Rotterdam, Netherlands..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Schmidt, Frank
    Ernst Moritz Arndt Univ Greifswald, Dept Funct Gen, Interfaculty Inst Genet & Funct Gen, Univ Med, D-17475 Greifswald, Germany..
    Smith, Albert Vernon
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Taylor, Kent D.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany..
    Thuesen, Betina H.
    Capital Region Denmark, Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark..
    Torstenson, Eric S.
    Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA..
    Tracy, Russell P.
    Univ Vermont Coll Med, Dept Pathol, Colchester, VT 05446 USA.;Univ Vermont Coll Med, Dept Lab Med, Colchester, VT 05446 USA.;Univ Vermont Coll Med, Dept Biochem, Colchester, VT 05446 USA..
    Tzoulaki, Ioanna
    Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina 45110, Greece..
    Zakai, Neil A.
    Univ Vermont Coll Med, Dept Med, Burlington, VT 05405 USA.;Univ Vermont Coll Med, Dept Pathol, Burlington, VT 05405 USA..
    Vacchi-Suzzi, Caterina
    SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA..
    van Duijn, Cornelia M.
    Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands..
    van Rooij, Frank J. A.
    Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands..
    Cushman, Mary
    Univ Vermont Coll Med, Dept Med, Burlington, VT 05405 USA.;Univ Vermont Coll Med, Dept Pathol, Burlington, VT 05405 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Edwards, Digna R. Velez
    Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Dept Obstet & Gynecol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN 37203 USA..
    Vergnaud, Anne-Claire
    Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Waterworth, Dawn M.
    Genet Target Sci, GlaxoSmithKline, King Of Prussia, PA 19406 USA..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand.;Univ Auckland, Auckland 1142, New Zealand..
    Wilson, James G.
    Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10069 USA..
    Lange, Leslie A.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Faraday, Nauder
    Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA..
    Abumrad, Nada A.
    Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA..
    Edwards, Todd L.
    Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA..
    Ganesh, Santhi K.
    Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA..
    Auer, Paul L.
    Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA..
    Johnson, Andrew D.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Reiner, Alexander P.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Lettre, Guillaume
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada..
    Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 1, p. 8-21Article in journal (Refereed)
    Abstract [en]

    Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 x 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 x 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 x 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

  • 10. Clemente, Florian J
    et al.
    Cardona, Alexia
    Inchley, Charlotte E
    Peter, Benjamin M
    Jacobs, Guy
    Pagani, Luca
    Lawson, Daniel J
    Antão, Tiago
    Vicente, Mário
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Mitt, Mario
    DeGiorgio, Michael
    Faltyskova, Zuzana
    Xue, Yali
    Ayub, Qasim
    Szpak, Michal
    Mägi, Reedik
    Eriksson, Anders
    Manica, Andrea
    Raghavan, Maanasa
    Rasmussen, Morten
    Rasmussen, Simon
    Willerslev, Eske
    Vidal-Puig, Antonio
    Tyler-Smith, Chris
    Villems, Richard
    Nielsen, Rasmus
    Metspalu, Mait
    Malyarchuk, Boris
    Derenko, Miroslava
    Kivisild, Toomas
    A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations.2014In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 95, no 5Article in journal (Refereed)
    Abstract [en]

    Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) in CPT1A, a key regulator of mitochondrial long-chain fatty-acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6-23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment.

  • 11.
    Dahlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tiwari, Neha
    Schuster, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Badhai, Jitendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pujol, Ramon
    van Steensel, Maurice A. M.
    Brinkhuizen, Tjinta
    Gijezen, Lieke
    Chaves, Antonio
    Tadini, Gianluca
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 4, p. 596-603Article in journal (Refereed)
    Abstract [en]

    KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.

  • 12. Devoto, M.
    et al.
    Castagnola, S.
    Saha, N.
    Chetsanga, C.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Romeo, G.
    Screening for the major cystic fibrosis mutation in non-Caucasian populations1991In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 49, no 4, p. 903-4Article in journal (Refereed)
  • 13.
    Dumanski, Jan P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lambert, Jean-Charles
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Davies, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grenier-Boley, Benjamin
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Broad Inst MIT, Cambridge, MA 02142 USA.;Harvard Univ, Cambridge, MA 02142 USA..
    Campion, Dominique
    Rouen Univ Hosp, INSERM, CNR MAJ, U1079, F-76031 Rouen, France..
    Dufouil, Carole
    Victor Segalen Univ, INSERM, U708, F-33076 Bordeaux, France..
    Pasquier, Florence
    Univ Lille, CNR MAJ, Inserm 1171, F-59000 Lille, France.;CHU Lille, F-59000 Lille, France..
    Amouyel, Philippe
    Univ Lille, INSERM, CHU Lille, Pasteur Lille,U1167,RID AGE Risk Factors & Mol De, F-59000 Lille, France..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Forsberg, Lars A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 98, no 6, p. 1208-1219Article in journal (Refereed)
    Abstract [en]

    Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.

  • 14.
    Ebarasi, Lwaki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ashraf, Shazia
    Bierzynska, Agnieszka
    Gee, Heon Yung
    McCarthy, Hugh J.
    Lovric, Svjetlana
    Sadowski, Carolin E.
    Pabst, Werner
    Vega-Warner, Virginia
    Fang, Humphrey
    Koziell, Ania
    Simpson, Michael A.
    Dursun, Ismail
    Serdaroglu, Erkin
    Levy, Shawn
    Saleem, Moin A.
    Hildebrandt, Friedhelm
    Majumdar, Arindam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Defects of CRB2 Cause Steroid-Resistant Nephrotic Syndrome2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 1, p. 153-161Article in journal (Refereed)
    Abstract [en]

    Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.

  • 15.
    Eicher, John D.
    et al.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Chami, Nathalie
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Kacprowski, Tim
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Mortiz Arndt Univ Greifswald, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Nomura, Akihiro
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Kanazawa Univ, Div Cardiovasc Med, Grad Sch Med Sci, Kanazawa, Ishikawa 9200942, Japan.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Chen, Ming-Huei
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Yanek, Lisa R.
    Johns Hopkins Univ, Div Gen Internal Med, Dept Med, Sch Med, Baltimore, MD 21205 USA..
    Tajuddin, Salman M.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Schick, Ursula M.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Slater, Andrew J.
    GlaxoSmithKline, Genet, Target Sci, Res Triangle Pk, NC 27709 USA.;OmicSoft Corp, Cary, NC 27513 USA..
    Pankratz, Nathan
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA..
    Polfus, Linda
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Giri, Ayush
    Vanderbilt Univ, Inst Med & Publ Hlth, Div Epidemiol, Nashville, TN 37235 USA..
    Brody, Jennifer A.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Lange, Leslie A.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Manichaikul, Ani
    Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA..
    Hill, W. David
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Pazoki, Raha
    Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands..
    Elliot, Paul
    Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England..
    Evangelou, Evangelos
    Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina 45110, Greece..
    Tzoulaki, Ioanna
    Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England.;Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina 45110, Greece..
    Gao, He
    Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England..
    Vergnaud, Anne-Claire
    Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England..
    Mathias, Rasika A.
    Johns Hopkins Univ, Div Gen Internal Med, Dept Med, Sch Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Immunol, Baltimore, MD 21205 USA..
    Becker, Diane M.
    Johns Hopkins Univ, Div Gen Internal Med, Dept Med, Sch Med, Baltimore, MD 21205 USA..
    Becker, Lewis C.
    Johns Hopkins Univ, Div Gen Internal Med, Dept Med, Sch Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Div Cardiol, Dept Med, Sch Med, Baltimore, MD 21205 USA..
    Burt, Amber
    Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA..
    Crosslin, David R.
    Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98105 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland..
    Nikus, Kjell
    Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland.;Univ Tampere, Sch Med, Tampere 33514, Finland..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland.;Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Dept Clin Physiol, Tampere 33514, Finland..
    Raitoharju, Emma
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland..
    Mononen, Nina
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland..
    Cushman, Mary
    Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA.;Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA..
    Zakai, Neil A.
    Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA.;Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA..
    Nickerson, Deborah A.
    Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA..
    Raffield, Laura M.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Quarells, Rakale
    Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA..
    Willer, Cristen J.
    Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48108 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Dept Human Genet, Ann Arbor, MI 48108 USA.;Univ Michigan, Dept Biostat, Ann Arbor, MI 48108 USA..
    Peloso, Gina M.
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48108 USA..
    Liu, Dajiang J.
    Penn State Univ Hosp, Dept Publ Hlth Sci, Coll Med, Hershey, PA 17033 USA..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, London E1 4NS, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England..
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80333 Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80333 Munich, Germany..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, D-23562 Lubeck, Germany..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Richard, Melissa
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Tardif, Jean-Claude
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Rioux, John D.
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Dube, Marie-Pierre
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    de Denus, Simon
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Fac Pharm, Montreal H3T 1J4, PQ, Canada..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Smith, Albert Vernon
    Icelandic Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Baltimore, MD 21224 USA..
    Launer, Lenore J.
    NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Baltimore, MD 21224 USA..
    Gudnason, Vilmundur
    Icelandic Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Edwards, Digna R. Velez
    Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Dept Obstet & Gynecol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN 37203 USA..
    Torstenson, Eric S.
    Vanderbilt Univ, Inst Med & Publ Hlth, Div Epidemiol, Nashville, TN 37235 USA..
    Liu, Yongmei
    Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA..
    Tracy, Russell P.
    Univ Vermont, Coll Med, Dept Pathol & Lab Med, Colchester, VT 05446 USA.;Univ Vermont, Coll Med, Dept Biochem, Colchester, VT 05446 USA..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Rich, Stephen S.
    Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA..
    Highland, Heather M.
    Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Univ Texas Sch Publ Hlth, Houston, TX 77030 USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Li, Jin
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA..
    Lange, Ethan
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA..
    Wilson, James G.
    Univ Mississippi, Dept Physiol & Biophys, Med Ctr, Jackson, MS 39216 USA..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Hirschhorn, Joel
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Vacchi-Suzzi, Caterina
    SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA..
    Nalls, Mike A.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 21224 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Engstrom, Gunnar
    Lund Univ, Dept Clin Sci Malmo, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci Malmo, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    Melander, Olle
    Lund Univ, Dept Clin Sci Malmo, S-22100 Malmo, Sweden.;Skane Univ Hosp, S-22241 Malmo, Sweden..
    O'Donoghue, Michelle L.
    Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA..
    Waterworth, Dawn M.
    GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand.;Univ Auckland, Auckland 1142, New Zealand..
    Floyd, James S.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rice, Kenneth M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA..
    Starr, J. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Hayward, Caroline
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Greinacher, Andreas
    Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany..
    Volker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Mortiz Arndt Univ Greifswald, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany..
    Thiele, Thomas
    Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany..
    Volzke, Henry
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, D-13347 Greifswald, Germany..
    van Rooij, Frank J. A.
    Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands.;Netherlands Consortium Hlth Ageing, NL-3015 Rotterdam, Netherlands..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands..
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands..
    Edwards, Todd L.
    Vanderbilt Univ, Inst Med & Publ Hlth, Div Epidemiol, Nashville, TN 37235 USA..
    Ganesh, Santhi K.
    Univ Michigan, Dept Internal & Human Genet, Ann Arbor, MI 48108 USA..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA..
    Faraday, Nauder
    Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Auer, Paul L.
    Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Reiner, Alex P.
    Univ Washington, Dept Epidemiol, Seattle, WA 98105 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Lettre, Guillaume
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Johnson, Andrew D.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 1, p. 40-55Article in journal (Refereed)
    Abstract [en]

    Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

  • 16. Foo, Jia Nee
    et al.
    Smedby, Karin E.
    Akers, Nicholas K.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Irwan, Ishak D.
    Jia, Xiaoming
    Li, Yi
    Conde, Lucia
    Darabi, Hatef
    Bracci, Paige M.
    Melbye, Mads
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Khor, Chiea Chuen
    Hjalgrim, Henrik
    Padyukov, Leonid
    Humphreys, Keith
    Enblad, Gunilla
    Skibola, Christine F.
    de Bakker, Paul I. W.
    Liu, Jianjun
    Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 1, p. 167-172Article in journal (Refereed)
    Abstract [en]

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 x 10(-15)). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 x 10(-14)). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

  • 17.
    Forsberg, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rasi, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Razzaghian, Hamid R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Pakalapati, Geeta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Waite, Lindsay
    Thilbeault, Krista Stanton
    Ronowicz, Anna
    Wineinger, Nathan E
    Tiwari, Hemant K
    Boomsma, Dorret
    Westerman, Maxwell P
    Harris, Jennifer R
    Lyle, Robert
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Assimes, Themistocles L
    Iribarren, Carlos
    Strachan, Eric
    O'Hanlon, Terrance P
    Rider, Lisa G
    Miller, Frederick W
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Piotrowski, Arkadiusz
    Pedersen, Nancy L
    Absher, Devin
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Age-related somatic structural changes in the nuclear genome of human blood cells2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 2, p. 217-228Article in journal (Refereed)
    Abstract [en]

    Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

  • 18.
    Fröjmark, Anne-Sophie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schuster, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Entesarian, Miriam
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kilander, Michaela B C
    Gabrikova, Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nawaz, Sadia
    Baig, Shahid M
    Schulte, Gunnar
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutations in frizzled 6 cause isolated autosomal-recessive nail dysplasia2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 6, p. 852-860Article in journal (Refereed)
    Abstract [en]

    Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways.

  • 19. Grundberg, Elin
    et al.
    Meduri, Eshwar
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hedman, Asa K.
    Keildson, Sarah
    Buil, Alfonso
    Busche, Stephan
    Yuan, Wei
    Nisbet, James
    Sekowska, Magdalena
    Wilk, Alicja
    Barrett, Amy
    Small, Kerrin S.
    Ge, Bing
    Caron, Maxime
    Shin, So-Youn
    Lathrop, Mark
    Dermitzakis, Emmanouil T.
    McCarthy, Mark I.
    Spector, Timothy D.
    Bell, Jordana T.
    Deloukas, Panos
    Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 876-890Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.

  • 20. Grundberg, Elin
    et al.
    Meduri, Eshwar
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedman, Åsa K.
    Wellcome Trust Centre for Human Genetics, University of Oxford, OX37BN Oxford, UK.
    Keildson, Sarah
    Buil, Alfonso
    Busche, Stephan
    Yuan, Wei
    Nisbet, James
    Sekowska, Magdalena
    Wilk, Alicja
    Barrett, Amy
    Small, Kerrin S.
    Ge, Bing
    Caron, Maxime
    Shin, So-Youn
    Lathrop, Mark
    Dermitzakis, Emmanouil T.
    McCarthy, Mark I.
    Spector, Timothy D.
    Bell, Jordana T.
    Deloukas, Panos
    Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 876-890Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.

  • 21. Hemani, Gibran
    et al.
    Yang, Jian
    Vinkhuyzen, Anna
    Powell, Joseph E.
    Willemsen, Gonneke
    Hottenga, Jouke-Jan
    Abdellaoui, Abdel
    Mangino, Massimo
    Valdes, Ana M.
    Medland, Sarah E.
    Madden, Pamela A.
    Heath, Andrew C.
    Henders, Anjali K.
    Nyholt, Dale R.
    de Geus, Eco J. C.
    Magnusson, Patrik K. E.
    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.
    Montgomery, Grant W.
    Spector, Timothy D.
    Boomsma, Dorret I.
    Pedersen, Nancy L.
    Martin, Nicholas G.
    Visscher, Peter M.
    Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 865-875Article in journal (Refereed)
    Abstract [en]

    Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 x 10(-7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific-linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 x 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.

  • 22. Hu, Yi-Juan
    et al.
    Berndt, Sonja I.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hirschhorn, Joel
    North, Kari E.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lin, Dan-Yu
    Meta-analysis of Gene-Level Associations for Rare Variants Based on Single-Variant Statistics2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 2, p. 236-248Article in journal (Refereed)
    Abstract [en]

    Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recoVered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

  • 23. Isidor, Bertrand
    et al.
    Pichon, Olivier
    Redon, Richard
    Day-Salvatore, Debra
    Hamel, Antoine
    Siwicka, Karolina A.
    Bitner-Glindzicz, Maria
    Heymann, Dominique
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kraus, Cornelia
    Leroy, Jules G.
    Mortier, Geert R.
    Rauch, Anita
    Verloes, Alain
    David, Albert
    Le Caignec, Cedric
    Mesomelia-Synostoses Syndrome Results from Deletion of SULF1 and SLCO5A1 Genes at 8q132010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 87, no 1, p. 95-100Article in journal (Refereed)
    Abstract [en]

    Mesomelia-synostoses syndrome (MSS) or mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type is a rare autosomal-dominant disorder characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations. So far, five patients in four unrelated families have been reported worldwide with MMS. By using whole-genome oligonucleotide array CGH, we have identified an interstitial deletion at 8q13 in all patients. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1, encoding the heparan sulfate 6-O-endosulfatase 1, and SLCO5A1, encoding the solute carrier organic anion transporter family member 5A1. SULF1 acts as a regulator of numerous growth factors in skeletal embryonic development whereas the function of SLCO5A1 is yet unknown. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Real-time quantitative RT-PCR analysis showed the highest levels of SULF1 transcripts in human osteoblasts and cartilage whereas SLCO5A1 was highly expressed in human fetal and adult brain and heart. Our results strongly suggest that haploinsufficiency of SULF1 contributes to this mesomelic chondrodysplasia, highlighting the critical role of endosulfatase in human skeletal development. Codeletion of SULF1 and SLCO5A1-which does not result from a low-copy repeats (LCRs)-mediated recombination event in at least two families-was found in all patients, so we suggest that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

  • 24.
    Klar, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Schweiger, Martina
    Zimmerman, Robert
    Zechner, Rudolf
    Li, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Vahlquist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Bouadjar, Bakar
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fischer, Judith
    Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity syndrome2009In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 85, no 2, p. 248-253Article in journal (Refereed)
    Abstract [en]

    Ichthyosis prematurity syndrome (IPS) is an autosomal-recessive disorder characterized by premature birth and neonatal asphyxia, followed by a lifelong nonscaly ichthyosis with atopic manifestations. Here we show that the gene encoding the fatty acid transport protein 4 (FATP4) is mutated in individuals with IPS. Fibroblasts derived from a patient with IPS show reduced activity of very long-chain fatty acids (VLCFA)-CoA synthetase and a specific reduction in the incorporation of VLCFA into cellular lipids. The human phenotype is consistent with Fatp4 deficiency in mice that is characterized by a severe skin phenotype, a defective permeability barrier function, and perturbed VLCFA metabolism. Our results further emphasize the importance of fatty acid metabolism for normal epidermal barrier function illustrated by deficiency of a member in the FATP family of proteins.

  • 25. Källberg, Henrik
    et al.
    Padyukov, Leonid
    Plenge, Robert M.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Gregersen, Peter K.
    van der Helm-van Mil, Annette H. M.
    Toes, Rene E.M.
    Huizinga, Tom W.
    Klareskog, Lars
    Alfredsson, Lars
    Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis2007In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 80, no 5, p. 867-875Article in journal (Refereed)
    Abstract [en]

    Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA—the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele—in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. “Interaction” was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium—for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP–positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP–positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.

  • 26.
    Lagerström-Fermér, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Sundvall, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Johnsen, Elsy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Warne, GL
    Forrest, SM
    Zajac, JD
    Richards, A
    Ravine, D
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    X-linked recessive panhypopituitarism associated with a regional duplication in Xq25-q261997In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 60, no 4, p. 910-916Article in journal (Refereed)
    Abstract [en]

    We present a linkage analysis and a clinical update on a previously reported family with X-linked recessive panhypopituitarism, now in its fourth generation. Affected members exhibit variable degrees of hypopituitarism and mental retardation. The markers DXS737 and DXS1187 in the q25-q26 region of the X chromosome showed evidence for linkage with a peak LOD score (Zmax) of 4.12 at zero recombination fraction (theta(max) = 0). An apparent extra copy of the marker DXS102, observed in the region of the disease gene in affected males and heterozygous carrier females, suggests that a segment including this marker is duplicated. The gene causing this disorder appears to code for a dosage-sensitive protein central to development of the pituitary.

  • 27. Lessard, Christopher J.
    et al.
    Adrianto, Indra
    Ice, John A.
    Wiley, Graham B.
    Kelly, Jennifer A.
    Glenn, Stuart B.
    Adler, Adam J.
    Li, He
    Rasmussen, Astrid
    Williams, Adrienne H.
    Ziegler, Julie
    Comeau, Mary E.
    Marion, Miranda
    Wakeland, Benjamin E.
    Liang, Chaoying
    Ramos, Paula S.
    Grundahl, Kiely M.
    Gallant, Caroline J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Alarcon-Riquelme, Marta E.
    Alarcon, Graciela S.
    Anaya, Juan-Manuel
    Bae, Sang-Cheol
    Boackle, Susan A.
    Brown, Elizabeth E.
    Chang, Deh-Ming
    Cho, Soo-Kyung
    Criswell, Lindsey A.
    Edberg, Jeffrey C.
    Freedman, Barry I.
    Gilkeson, Gary S.
    Jacob, Chaim O.
    James, Judith A.
    Kamen, Diane L.
    Kimberly, Robert P.
    Kim, Jae-Hoon
    Martin, Javier
    Merrill, Joan T.
    Niewold, Timothy B.
    Park, So-Yeon
    Petri, Michelle A.
    Pons-Estel, Bernardo A.
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Scofield, R. Hal
    Song, Yeong Wook
    Stevens, Anne M.
    Tsao, Betty P.
    Vila, Luis M.
    Vyse, Timothy J.
    Yu, Chack-Yung
    Guthridge, Joel M.
    Kaufman, Kenneth M.
    Harley, John B.
    Wakeland, Edward K.
    Langefeld, Carl D.
    Gaffney, Patrick M.
    Montgomery, Courtney G.
    Moser, Kathy L.
    Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 4, p. 648-660Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 x 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) 8.62 x 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 x 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 x 10(-8) < p(meta-Euro) < 9.99 x 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4 FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.

  • 28. Lessard, Christopher J.
    et al.
    Adrianto, Indra
    Kelly, Jennifer A.
    Kaufman, Kenneth M.
    Grundahl, Kiely M.
    Adler, Adam
    Williams, Adrienne H.
    Gallant, Caroline J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Alarcon-Riquelme, Marta E.
    Anaya, Juan-Manuel
    Bae, Sang-Cheol
    Boackle, Susan A.
    Brown, Elizabeth E.
    Chang, Deh-Ming
    Criswell, Lindsey A.
    Edberg, Jeffrey C.
    Freedman, Barry I.
    Gregersen, Peter K.
    Gilkeson, Gary S.
    Jacob, Chaim O.
    James, Judith A.
    Kamen, Diane L.
    Kimberly, Robert P.
    Martin, Javier
    Merrill, Joan T.
    Niewold, Timothy B.
    Park, So-Yeon
    Petri, Michelle A.
    Pons-Estel, Bernardo A.
    Ramsey-Goldman, Rosalind
    Reveille, John D.
    Song, Yeong Wook
    Stevens, Anne M.
    Tsao, Betty P.
    Vila, Luis M.
    Vyse, Timothy J.
    Yu, Chack-Yung
    Guthridge, Joel M.
    Bruner, Gail R.
    Langefeld, Carl D.
    Montgomery, Courtney
    Harley, John B.
    Scofield, R. Hal
    Gaffney, Patrick M.
    Moser, Kathy L.
    Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 1, p. 83-91Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 x 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 x 10(-8), OR = 0.83) and rs387619 (p = 7.7 x 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 x 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 x 10(-3), OR = 0.81 and p = 4.3 x 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 x 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.

  • 29. Lewis, Cathryn M
    et al.
    Levinson, Douglas F
    Wise, Lesley H
    DeLisi, Lynn E
    Straub, Richard E
    Hovatta, Iiris
    Williams, Nigel M
    Schwab, Sibylle G
    Pulver, Ann E
    Faraone, Stephen V
    Brzustowicz, Linda M
    Kaufmann, Charles A
    Garver, David L
    Gurling, Hugh M D
    Lindholm, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Coon, Hilary
    Moises, Hans W
    Byerley, William
    Shaw, Sarah H
    Mesen, Andrea
    Sherrington, Robin
    O'Neill, F Anthony
    Walsh, Dermot
    Kendler, Kenneth S
    Ekelund, Jesper
    Paunio, Tiina
    Lännqvist, Jouko
    Peltonen, Leena
    O'Donovan, Michael C
    Owen, Michael J
    Wildenauer, Dieter B
    Maier, Wolfgang
    Nestadt, Gerald
    Blouin, Jean-Louis
    Antonarakis, Stylianos E
    Mowry, Bryan J
    Silverman, Jeremy M
    Crowe, Raymond R
    Cloninger, C Robert
    Tsuang, Ming T
    Malaspina, Dolores
    Harkavy-Friedman, Jill M
    Svrakic, Dragan M
    Bassett, Anne S
    Holcomb, Jennifer
    Kalsi, Gursharan
    McQuillin, Andrew
    Brynjolfson, Jon
    Sigmundsson, Thordur
    Petursson, Hannes
    Jazin, Elena
    Zoëga, Tomas
    Helgason, Tomas
    Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia2003In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Am J Hum Genet, ISSN 0002-9297, Vol. 73, no 1, p. 34-48Article in journal (Refereed)
    Abstract [en]

    Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.

  • 30.
    Lindholm, Eva
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Ekholm, Birgit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Shaw, Sarah
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jalonen, Paula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Johansson, Gunnel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Sherrington, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Adolfsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees2001In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 69, no 1, p. 96-105Article in journal (Refereed)
  • 31.
    Mahajan, Anubha
    et al.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
    Rodan, Aylin R.
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75229 USA.
    Le, Thu H.
    Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    Gaulton, Kyle J.
    Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
    Haessler, Jeffrey
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    Stilp, Adrienne M.
    Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
    Kamatani, Yoichiro
    Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
    Zhu, Gu
    Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
    Sofer, Tamar
    Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
    Puri, Sanjana
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75229 USA.
    Schellinger, Jeffrey N.
    Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75229 USA.
    Chu, Pei-Lun
    Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    Cechova, Sylvia
    Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
    van Zuydam, Natalie
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. School of Health and Social Studies, Dalarna University, Falun 791 88, Sweden.
    Flessner, Michael F.
    National Institute of Diabetes, Digestive, and Kidney Disease, NIH, Bethesda, MD 20892, USA.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Heath, Andrew C.
    Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
    Kubo, Michiaki
    Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7BN, UK.
    Madden, Pamela A. F.
    Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA.
    Montgomery, Grant W.
    Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
    Papanicolaou, George J.
    Epidemiology Branch, Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
    Reiner, Alex P.
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Thornton, Timothy A.
    Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
    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, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
    Cai, Jianwen
    Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
    Martin, Nicholas G.
    Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
    Kooperberg, Charles
    Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
    Matsuda, Koichi
    Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
    Whitfield, John B.
    Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
    Okada, Yukinori
    Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
    Laurie, Cathy C.
    Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England; Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
    Franceschini, Nora
    Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514, USA.
    Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 3, p. 636-646Article in journal (Refereed)
    Abstract [en]

    We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.

  • 32.
    Manousaki, Despoina
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada..
    Dudding, Tom
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Haworth, Simon
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02142 USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Medina-Gomez, Carolina
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Voortman, Trudy
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Acad Med Ctr, Dept Internal Med, Sect Geriatr, NL-1105 AZ Amsterdam, Netherlands..
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Robinson-Cohen, Cassianne
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA..
    Cousminer, Diana L.
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA..
    Nethander, Maria
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Bioinformat Core Facil, S-41390 Gothenburg, Sweden..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden..
    Noordam, Raymond
    Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, NL-2333 ZA Leiden, Netherlands..
    Forgetta, Vincenzo
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada..
    Greenwood, Celia M. T.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.;McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 1A2, Canada.;McGill Univ, Dept Oncol, Montreal, PQ H4A 3T2, Canada..
    Biggs, Mary L.
    Univ Washington, Dept Med & Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Kaiser Permanente Washington Hlth Res Unit, Seattle, WA 98101 USA..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Zemel, Babette S.
    Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA..
    Mitchell, Jonathan A.
    Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA..
    Taylor, Bruce
    Univ Tasmania, Menzies Inst Med Res, Locked Bag 23, Hobart, Tas 7000, Australia..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, Geriatr Med, S-43180 Molndal, Sweden..
    Karlsson, Magnus
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, S-22241 Malmo, Sweden.;Skane Univ Hosp, Dept Orthopaed, S-22241 Malmo, Sweden..
    Jaddoe, Vincent V. W.
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Tiemeier, Henning
    Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Child & Adolescent Psychiat Psychol, NL-3015 GE Rotterdam, Netherlands..
    Campos-Obando, Natalia
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Utterlinden, Andre G.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Broer, Linda
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    van Schoor, Natasja M.
    Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands..
    Ham, Annelies C.
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Radiol & Nucl Med, NL-3015 GE Rotterdam, Netherlands..
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA..
    de Mutsert, Renee
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands..
    Rosendaal, Frits R.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands..
    den Heijer, Martin
    Vrije Univ Amsterdam, Med Ctr, Dept Endocrinol, NL-1081 HV Amsterdam, Netherlands..
    Wang, Thomas J.
    Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Orwoll, Eric S.
    Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2333 ZA Leiden, Netherlands..
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kestenbaum, Bryan
    Univ Washington, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden..
    Mellström, Dan K
    Univ Gothenburg, Sahlgrenska Acad, Inst Med,Ctr Bone & Arthrit, Dept Internal Med & Clin Nutr, S-40530 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, S-43180 Molndal, Sweden..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Div Human Nutr, NL-6708 WE Wageningen, Netherlands..
    Grant, Struan F. A.
    Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Endocrinol, Philadelphia, PA 19104 USA..
    Kiel, Douglas P.
    Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02142 USA.;Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands..
    Rivadeneira, Fernando
    Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Generat R Study Grp, NL-3015 GE Rotterdam, Netherlands.;Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands..
    Sawcer, Stephen
    Univ Cambridge, Dept Clin Neurosci, Box 165,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England..
    Timpson, Nicholas J.
    Univ Bristol, Med Res Council, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Richards, J. Brent
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada.;McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England.;McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada..
    Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis2017In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 101, no 2, p. 227-238Article in journal (Refereed)
    Abstract [en]

    Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 x 10(-88)). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 3 10 x(-12)). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 3 10 x(-5)) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

  • 33. Maugeri, A.
    et al.
    van Driel, M.A.
    van de Pol, D.J.
    Klevering, B.J.
    van Haren, F.J.
    Tijmes, N.
    Bergen, A.A.
    Rohrschneider, K.
    Blankenagel, A.
    Pinckers, A.J.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Brunner, H.G.
    Deutman, A.F.
    Hoyng, C.B.
    Cremers, F.P.
    The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease1999In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 64, no 4, p. 1024-35Article in journal (Refereed)
    Abstract [en]

    In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.

  • 34. Miller, David T.
    et al.
    Adam, Margaret P.
    Aradhya, Swaroop
    Biesecker, Leslie G.
    Brothman, Arthur R.
    Carter, Nigel P.
    Church, Deanna M.
    Crolla, John A.
    Eichler, Evan E.
    Epstein, Charles J.
    Faucett, W. Andrew
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Friedman, Jan M.
    Hamosh, Ada
    Jackson, Laird
    Kaminsky, Erin B.
    Kok, Klaas
    Krantz, Ian D.
    Kuhn, Robert M.
    Lee, Charles
    Ostell, James M.
    Rosenberg, Carla
    Scherer, Stephen W.
    Spinner, Nancy B.
    Stavropoulos, Dimitri J.
    Tepperberg, James H.
    Thorland, Erik C.
    Vermeesch, Joris R.
    Waggoner, Darrel J.
    Watson, Michael S.
    Martin, Christa Lese
    Ledbetter, David H.
    Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 5, p. 749-764Article in journal (Refereed)
    Abstract [en]

    Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype (similar to 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

  • 35.
    Nielsen, Jonas B.
    et al.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Fritsche, Lars G.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Zhou, Wei
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Teslovich, Tanya M.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Holmen, Oddgeir L.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway..
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Gabrielsen, Maiken E.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Schmidt, Ellen M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Beaumont, Robin
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Wolford, Brooke N.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Lin, Maoxuan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Brummett, Chad M.
    Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA..
    Preuss, Michael H.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Refsgaard, Lena
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA..
    Graham, Sarah E.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Surakka, Ida
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Chu, Yunhan
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Skogholt, Anne Heidi
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Dalen, Havard
    St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, N-7491 Trondheim, Norway..
    Boyle, Alan P.
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Oral, Hakan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Herron, Todd J.
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Kitzman, Jacob
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Jalife, Jose
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA.;Fdn Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain..
    Svendsen, Jesper H.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark..
    Olesen, Morten S.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed, DK-2200 Copenhagen, Denmark..
    Njolstad, Inger
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Lochen, Maja-Lisa
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Baras, Aris
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Gottesman, Omri
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Marcketta, Anthony
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    O'Dushlaine, Colm
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Danville, PA 17822 USA..
    Wilsgaard, Tom
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Frayling, Timothy M.
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Boehnke, Michael
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Depart- ment of Medicine, Stanford University School of Medicine, Stanford, USA.
    Carey, David J.
    Dewey, Frederick E.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Kang, Hyun M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway..
    Willer, Cristen J.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 1, p. 103-115Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

  • 36. Ostergaard, Pia
    et al.
    Simpson, Michael A
    Mendola, Antonella
    Vasudevan, Pradeep
    Connell, Fiona C
    van Impel, Andreas
    Moore, Anthony T
    Loeys, Bart L
    Ghalamkarpour, Arash
    Onoufriadis, Alexandros
    Martinez-Corral, Ines
    Devery, Sophie
    Leroy, Jules G
    van Laer, Lut
    Singer, Amihood
    Bialer, Martin G
    McEntagart, Meriel
    Quarrell, Oliver
    Brice, Glen
    Trembath, Richard C
    Schulte-Merker, Stefan
    Makinen, Taija
    Vikkula, Miikka
    Mortimer, Peter S
    Mansour, Sahar
    Jeffery, Steve
    Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy.2012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 2Article in journal (Refereed)
    Abstract [en]

    We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.

  • 37. Palomares, Maria
    et al.
    Delicado, Alicia
    Mansilla, Elena
    Luisa de Torres, Maria
    Vallespin, Elena
    Fernandez, Luis
    Martinez-Glez, Victor
    Garcia-Minaur, Sixto
    Nevado, Julian
    Santos Simarro, Fernando
    Ruiz-Perez, Victor L.
    Lynch, Sally Ann
    Sharkey, Freddie H.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Belligni, Elga F.
    Luisa Martinez-Fernandez, Maria
    Bermejo, Eva
    Nowakowska, Beata
    Kutkowska-Kazmierczak, Anna
    Bocian, Ewa
    Obersztyn, Ewa
    Luisa Martinez-Frias, Maria
    Hennekam, Raoul C. M.
    Lapunzina, Pablo
    Characterization of a 8q21.11 Microdeletion Syndrome Associated with Intellectual Disability and a Recognizable Phenotype2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 2, p. 295-301Article in journal (Refereed)
    Abstract [en]

    We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

  • 38. Rosser, Z H
    et al.
    Zerjal, T
    Hurles, M E
    Adojaan, M
    Alavantic, D
    Amorim, A
    Amos, W
    Armenteros, M
    Arroyo, E
    Barbujani, G
    Beckman, G
    Beckman, L
    Bertranpetit, J
    Bosch, E
    Bradley, D G
    Brede, G
    Cooper, G
    Côrte-Real, H B
    de Knijff, P
    Decorte, R
    Dubrova, Y E
    Evgrafov, O
    Gilissen, A
    Glisic, S
    Gölge, M
    Hill, E W
    Jeziorowska, A
    Kalaydjieva, L
    Kayser, M
    Kivisild, T
    Kravchenko, S A
    Krumina, A
    Kucinskas, V
    Lavinha, J
    Livshits, L A
    Malaspina, P
    Maria, S
    McElreavey, K
    Meitinger, T A
    Mikelsaar, A V
    Mitchell, R J
    Nafa, K
    Nicholson, J
    Nørby, S
    Pandya, A
    Parik, J
    Patsalis, P C
    Pereira, L
    Peterlin, B
    Pielberg, G
    Prata, M J
    Previderé, C
    Roewer, L
    Rootsi, S
    Rubinsztein, D C
    Saillard, J
    Santos, F R
    Stefanescu, G
    Sykes, B C
    Tolun, A
    Villems, R
    Tyler-Smith, C
    Jobling, M A
    Y-chromosomal diversity in Europe is clinal and influenced primarily by geography, rather than by language.2000In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 67, no 6, p. 1526-43Article in journal (Refereed)
    Abstract [en]

    Clinal patterns of autosomal genetic diversity within Europe have been interpreted in previous studies in terms of a Neolithic demic diffusion model for the spread of agriculture; in contrast, studies using mtDNA have traced many founding lineages to the Paleolithic and have not shown strongly clinal variation. We have used 11 human Y-chromosomal biallelic polymorphisms, defining 10 haplogroups, to analyze a sample of 3,616 Y chromosomes belonging to 47 European and circum-European populations. Patterns of geographic differentiation are highly nonrandom, and, when they are assessed using spatial autocorrelation analysis, they show significant clines for five of six haplogroups analyzed. Clines for two haplogroups, representing 45% of the chromosomes, are continentwide and consistent with the demic diffusion hypothesis. Clines for three other haplogroups each have different foci and are more regionally restricted and are likely to reflect distinct population movements, including one from north of the Black Sea. Principal-components analysis suggests that populations are related primarily on the basis of geography, rather than on the basis of linguistic affinity. This is confirmed in Mantel tests, which show a strong and highly significant partial correlation between genetics and geography but a low, nonsignificant partial correlation between genetics and language. Genetic-barrier analysis also indicates the primacy of geography in the shaping of patterns of variation. These patterns retain a strong signal of expansion from the Near East but also suggest that the demographic history of Europe has been complex and influenced by other major population movements, as well as by linguistic and geographic heterogeneities and the effects of drift.

  • 39.
    Sigurdsson, Snaevar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göring, Harald
    Lindroos, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wiman, Ann-Christin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sturfelt, Gunnar
    Jönsen, Andreas
    Rantapää-Dahlqvist, Solbritt
    Möller, Bozena
    Kere, Juha
    Koskenmies, Sari
    Widen, Elisabeth
    Eloranta, Maija-Leena
    Julkunen, Heikki
    Kristjansdottir, Helga
    Steinsson, Kristjan
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, American Journal of Human Genetics, Vol. 76, no 3, p. 528-537Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.

  • 40. Skibola, Christine F.
    et al.
    Berndt, Sonja I.
    Vijai, Joseph
    Conde, Lucia
    Wang, Zhaoming
    Yeager, Meredith
    de Bakker, Paul I. W.
    Birmann, Brenda M.
    Vajdic, Claire M.
    Foo, Jia-Nee
    Bracci, Paige M.
    Vermeulen, Roel C. H.
    Slager, Susan L.
    de Sanjose, Silvia
    Wang, Sophia S.
    Linet, Martha S.
    Salles, Gilles
    Lan, Qing
    Severi, Gianluca
    Hjalgrim, Henrik
    Lightfoot, Tracy
    Melbye, Mads
    Gu, Jian
    Ghesquieres, Herve
    Link, Brian K.
    Morton, Lindsay M.
    Holly, Elizabeth A.
    Smith, Alex
    Tinker, Lesley F.
    Teras, Lauren R.
    Kricker, Anne
    Becker, Nikolaus
    Purdue, Mark P.
    Spinelli, John J.
    Zhang, Yawei
    Giles, Graham G.
    Vineis, Paolo
    Monnereau, Alain
    Bertrand, Kimberly A.
    Albanes, Demetrius
    Zeleniuch-Jacquotte, Anne
    Gabbas, Attilio
    Chung, Charles C.
    Burdett, Laurie
    Hutchinson, Amy
    Lawrence, Charles
    Montalvan, Rebecca
    Liang, Liming
    Huang, Jinyan
    Ma, Baoshan
    Liu, Jianjun
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ye, Yuanqing
    Nowakowski, Grzegorz S.
    Dogan, Ahmet
    Thompson, Carrie A.
    Habermann, Thomas M.
    Novak, Anne J.
    Liebow, Mark
    Witzig, Thomas E.
    Weiner, George J.
    Schenk, Maryjean
    Hartge, Patricia
    De Roos, Anneclaire J.
    Cozen, Wendy
    Zhi, Degui
    Akers, Nicholas K.
    Riby, Jacques
    Smith, Martyn T.
    Lacher, Mortimer
    Villano, Danylo J.
    Maria, Ann
    Roman, Eve
    Kane, Eleanor
    Jackson, Rebecca D.
    North, Kari E.
    Diver, W. Ryan
    Turner, Jenny
    Armstrong, Bruce K.
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Staines, Anthony
    McKay, James
    Brooks-Wilson, Angela R.
    Zheng, Tongzhang
    Holford, Theodore R.
    Chamosa, Saioa
    Kaaks, Rudolph
    Kelly, Rachel S.
    Ohlsson, Bodil
    Travis, Ruth C.
    Weiderpass, Elisabete
    Clave, Jacqueline
    Giovannucci, Edward
    Kraft, Peter
    Virtamo, Jarmo
    Mazza, Patrizio
    Cocco, Pierluigi
    Ennas, Maria Grazia
    Chiu, Brian C. H.
    Fraumeni, Joseph R., Jr.
    Nieters, Alexandra
    Offit, Kenneth
    Wu, Xifeng
    Cerhan, James R.
    Smedby, Karin E.
    Chanock, Stephen J.
    Rothman, Nathaniel
    Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region2014In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 95, no 4, p. 462-471Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 x 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 x 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 x 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 x 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 x 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DR beta 1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (P-omnibus = 4.20 x 10(-67) to 2.67 x 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 x 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 x 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

  • 41. Spiegel, Konen
    et al.
    Pines, Ophry
    Ta-Shma, Asaf
    Burak, Efrat
    Shaag, Avraham
    Halvardson, Jonatan
    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.
    Edvardson, Shimon
    Mahajna, Muhammad
    Zenvirt, Shamir
    Saada, Ann
    Shalev, Stavit
    Feuk, Lars
    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.
    Elpeleg, Orly
    Infantile Cerebellar-Retinal Degeneration Associated with a Mutation in Mitochondrial Aconitase, ACO22012In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, no 3, p. 518-523Article in journal (Refereed)
    Abstract [en]

    Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.

  • 42. Stattin, Eva-Lena
    et al.
    Wiklund, Fredrik
    Lindblom, Karin
    Önnerfjord, Patrik
    Jonsson, Björn-Anders
    Tegner, Yelverton
    Sasaki, Takako
    Struglics, Andre
    Lohmander, Stefan
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heinegård, Dick
    Aspberg, Anders
    A Missense Mutation in the Aggrecan C-type Lectin Domain Disrupts Extracellular Matrix Interactions and Causes Dominant Familial Osteochondritis Dissecans2010In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, no 2, p. 126-137Article in journal (Refereed)
    Abstract [en]

    Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.

  • 43. Syvänen, Ann-Christine
    et al.
    Sajantila, A
    Lukka, M
    Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing1993In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 52, no 1, p. 46-59Article in journal (Refereed)
    Abstract [en]

    We have developed a new method for forensic identification of individuals, in which a panel of biallelic DNA markers are amplified by the PCR, and the variable nucleotides are detected in the amplified DNA fragments by the solid-phase minisequencing method. A panel of 12 common polymorphic nucleotides located on different chromosomes with reported allele frequencies close to .5 were chosen for the test. The allele frequencies for most of the markers were found to be similar in the Finnish and other Caucasian populations. We also introduce a novel approach for rapid determination of the population frequencies of biallelic markers. By this approach we were able to determine the allele frequencies of the markers in the Finnish population, by quantitative analysis of three pooled DNA samples representing 3,000 individuals. The power of discrimination and exclusion of the solid-phase minisequencing typing test with 12 markers was similar to that of three VNTR markers that are routinely used in forensic analyses at our institute. The solid-phase minisequencing method was successfully applied to type paternity and forensic case samples. We also show that the quantitative nature of our method allows typing of mixed samples.

  • 44.
    Tajuddin, Salman M.
    et al.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Schick, Ursula M.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Eicher, John D.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Chami, Nathalie
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Giri, Ayush
    Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Brody, Jennifer A.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Hill, W. David
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Kacprowski, Tim
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Li, Jin
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland..
    Manichaikul, Ani
    Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    O'Donoghue, Michelle L.
    Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA..
    Pankratz, Nathan
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA..
    Pazoki, Raha
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Polfus, Linda M.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Smith, Albert Vernon
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Vacchi-Suzzi, Caterina
    SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA..
    Waterworth, Dawn M.
    GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA..
    Evangelou, Evangelos
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece..
    Yanek, Lisa R.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Burt, Amber
    Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA..
    Chen, Ming-Huei
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    van Rooij, Frank J. A.
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    Floyd, James S.
    Univ Washington, Dept Med, Seattle, WA 98101 USA..
    Greinacher, Andreas
    Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany..
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Highland, Heather M.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA..
    Lange, Leslie A.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Liu, Yongmei
    Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Nalls, Mike A.
    NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA..
    Mathias, Rasika A.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Nickerson, Deborah A.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98105 USA..
    Nikus, Kjell
    Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland.;Univ Tampere, Sch Med, Tampere 33014, Finland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Tardif, Jean-Claude
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Tzoulaki, Ioanna
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England.;Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece..
    Edwards, Digna R. Velez
    Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr,Dept Obstet & Gynecol, Nashville, TN 37203 USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Becker, Lewis C.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA..
    Denny, Joshua C.
    Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA..
    Raffield, Laura M.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA..
    Rioux, John D.
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Friedrich, Nele
    DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med Greifswald, Inst Clin Chem & Lab Med, D-13347 Greifswald, Germany..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Gao, He
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England..
    Hirschhorn, Joel N.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Rich, Stephen S.
    Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Uitterlinden, Andre
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands.;NCHA, NL-3015 GD Rotterdam, Netherlands..
    Bastarache, Lisa
    Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA..
    Becker, Diane M.
    Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    de Denus, Simon
    Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada.;Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany..
    Lange, Ethan
    Univ N Carolina, Dept Genet & Biostat, Chapel Hill, NC 27599 USA..
    Launer, Lenore J.
    NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    O'Donnell, Chris J.
    NHLBI, Framingham Heart Study, Framingham, MA 01702 USA.;Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02118 USA.;Boston Vet Adm Healthcare, Ctr Populat Genom, Boston, MA 02118 USA..
    Quarells, Rakale C.
    Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA..
    Richard, Melissa
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Torstenson, Eric S.
    Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Taylor, Kent D.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Vergnaud, Anne-Claire
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Crosslin, David R.
    Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland..
    Dorr, Marcus
    DZHK German Ctr Cardiovasc Res, Greifswald, Germany.;Univ Med Greifswald, Dept Cardiol, D-17475 Greifswald, Germany..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland.;Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland..
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA.;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Rotter, Jerome I.
    Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Slater, Andrew J.
    OmicSoft Corp, Cary, NC 27513 USA.;GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, NC 27709 USA..
    Dehghan, Abbas
    Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands..
    White, Harvey D.
    Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand.;Univ Auckland, Auckland 1142, New Zealand..
    Ganesh, Santhi K.
    Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Faraday, Nauder
    Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Cushman, Mary
    Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA..
    Johnson, Andrew D.
    NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA..
    Edwards, Todd L.
    Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Div Epidemiol,Dept Med, Nashville, TN 37203 USA..
    Zakai, Neil A.
    Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA..
    Lettre, Guillaume
    Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Reiner, Alex P.
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA..
    Auer, Paul L.
    Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA..
    Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases2016In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 99, no 1, p. 22-39Article in journal (Refereed)
    Abstract [en]

    White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of similar to 157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 ' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

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