Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Zari Dastani; Marie-France Hivert; Nicholas Timpson; John R. B. Perry; Xin Yuan; Robert A. Scott; Peter Henneman; Iris M. Heid; Jorge R. Kizer; Leo-Pekka Lyytikainen; Christian Fuchsberger; Toshiko Tanaka; Andrew P. Morris; Kerrin Small; Aaron Isaacs; Marian Beekman; Stefan Coassin; Kurt Lohman; Lu Qi; Stavroula Kanoni; James S. Pankow; Hae-Won Uh; Ying Wu; Aurelian Bidulescu; Laura J. Rasmussen-Torvik; Celia M. T. Greenwood; Martin Ladouceur; Jonna Grimsby; Alisa K. Manning; Ching-Ti Liu; Jaspal Kooner; Vincent E. Mooser; Peter Vollenweider; Karen A. Kapur; John Chambers; Nicholas J. Wareham; Claudia Langenberg; Rune Frants; Ko Willems-vanDijk; Ben A. Oostra; Sara M. Willems; Claudia Lamina; Thomas W. Winkler; Bruce M. Psaty; Russell P. Tracy; Jennifer Brody; Ida Chen; Jorma Viikari; Mika Kahonen; Peter P. Pramstaller; David M. Evans; Beate St Pourcain; Naveed Sattar; Andrew R. Wood; Stefania Bandinelli; Olga D. Carlson; Josephine M. Egan; Stefan Bohringer; Diana van Heemst; Lyudmyla Kedenko; Kati Kristiansson; Marja-Liisa Nuotio; Britt-Marie Loo; Tamara Harris; Melissa Garcia; Alka Kanaya; Margot Haun; Norman Klopp; H. -Erich Wichmann; Panos Deloukas; Efi Katsareli; David J. Couper; Bruce B. Duncan; Margreet Kloppenburg; Linda S. Adair; Judith B. Borja; James G. Wilson; Solomon Musani; Xiuqing Guo; Toby Johnson; Robert Semple; Tanya M. Teslovich; Matthew A. Allison; Susan Redline; Sarah G. Buxbaum; Karen L. Mohlke; Ingrid Meulenbelt; Christie M. Ballantyne; George V. Dedoussis; Frank B. Hu; Yongmei Liu; Bernhard Paulweber; Timothy D. Spector; P. Eline Slagboom; Luigi Ferrucci; Antti Jula; Markus Perola; Olli Raitakari; Jose C. Florez; Veikko Salomaa; Johan G. Eriksson; Timothy M. Frayling; Andrew A. Hicks; Terho Lehtimaki; George Davey Smith; David S. Siscovick; Florian Kronenberg; Cornelia van Duijn; Ruth J. F. Loos; Dawn M. Waterworth; James B. Meigs; Josee Dupuis; J. Brent Richards; GLGC Investigators

doi:10.1371/journal.pgen.1002607

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Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

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Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R. B. Perry, Xin Yuan, Robert A. Scott, Peter Henneman, Iris M. Heid, Jorge R. Kizer, Leo-Pekka Lyytikainen, …

PLoS genetics, Vol.8(3), pp.e1002607-e1002607

2012

DOI: https://doi.org/10.1371/journal.pgen.1002607

PMCID: PMC3315470

PMID: 22479202

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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

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Title: Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals
Creators - without role: Zari Dastani - McGill University
Marie-France Hivert - Université de Sherbrooke
Nicholas Timpson - University of Bristol
John R. B. Perry - Peninsula College of Medicine and Dentistry
Xin Yuan - GlaxoSmithKline
Robert A. Scott - MRC Epidemiology Unit
Peter Henneman - Leiden University Medical Center
Iris M. Heid - University of Regensburg
Jorge R. Kizer - College Station Medical Center
Leo-Pekka Lyytikainen - Tampere University Hospital
Christian Fuchsberger - University of Michigan–Ann Arbor
Toshiko Tanaka - National Institute on Aging
Andrew P. Morris - Wellcome Centre for Human Genetics
Kerrin Small - King's College London
Aaron Isaacs - Erasmus MC
Marian Beekman - Leiden University Medical Center
Stefan Coassin - Innsbruck Medical University
Kurt Lohman - Wake Forest University
Lu Qi - Harvard University
Stavroula Kanoni - Wellcome Sanger Institute
James S. Pankow - University of Minnesota
Hae-Won Uh - Leiden University Medical Center
Ying Wu - University of North Carolina at Chapel Hill
Aurelian Bidulescu - Morehouse School of Medicine
Laura J. Rasmussen-Torvik - Northwestern University
Celia M. T. Greenwood - McGill University
Martin Ladouceur - McGill University
Jonna Grimsby - Massachusetts General Hospital
Alisa K. Manning - Boston University
Ching-Ti Liu - Boston University
Jaspal Kooner - National Health Service
Vincent E. Mooser - GlaxoSmithKline
Peter Vollenweider - University of Lausanne
Karen A. Kapur - University of Lausanne
John Chambers - Imperial College London
Nicholas J. Wareham - MRC Epidemiology Unit
Claudia Langenberg - MRC Epidemiology Unit
Rune Frants - Leiden University Medical Center
Ko Willems-vanDijk - Leiden University Medical Center
Ben A. Oostra - Erasmus MC
Sara M. Willems - Erasmus MC
Claudia Lamina - Innsbruck Medical University
Thomas W. Winkler - University of Regensburg
Bruce M. Psaty - University of Washington
Russell P. Tracy - University of Vermont
Jennifer Brody - University of Washington
Ida Chen - Cedars-Sinai Medical Center
Jorma Viikari - University of Turku
Mika Kahonen - Tampere University Hospital
Peter P. Pramstaller - University of Lübeck
David M. Evans - University of Bristol
Beate St Pourcain - University of Bristol
Naveed Sattar - University of Glasgow
Andrew R. Wood - Peninsula College of Medicine and Dentistry
Stefania Bandinelli - Azienda Sanitaria di Firenze
Olga D. Carlson - National Institute on Aging
Josephine M. Egan - National Institute on Aging
Stefan Bohringer - Leiden University Medical Center
Diana van Heemst - Leiden University Medical Center
Lyudmyla Kedenko - Paracelsus Medical University
Kati Kristiansson - Institute for Molecular Medicine Finland
Marja-Liisa Nuotio - Institute for Molecular Medicine Finland
Britt-Marie Loo - Finnish Institute for Health and Welfare
Tamara Harris - National Institute on Aging
Melissa Garcia - National Institute on Aging
Alka Kanaya - University of California, San Francisco
Margot Haun - Innsbruck Medical University
Norman Klopp - Helmholtz Zentrum München
H. -Erich Wichmann - Zimmer Biomet
Panos Deloukas - Wellcome Sanger Institute
Efi Katsareli - Harokopio University of Athens
David J. Couper - University of North Carolina at Chapel Hill
Bruce B. Duncan - Universidade Federal do Rio Grande do Sul
Margreet Kloppenburg - Dept Rheumatol, Leiden, Netherlands
Linda S. Adair - University of North Carolina at Chapel Hill
Judith B. Borja - University of San Carlos
James G. Wilson - University of Mississippi Medical Center
Solomon Musani - University of Mississippi Medical Center
Xiuqing Guo - Cedars-Sinai Medical Center
Toby Johnson - University of Lausanne
Robert Semple - Addenbrooke's Hospital
Tanya M. Teslovich - University of Michigan–Ann Arbor
Matthew A. Allison - University of California, San Diego
Susan Redline - Brigham and Women's Hospital
Sarah G. Buxbaum - Jackson State University
Karen L. Mohlke - University of North Carolina at Chapel Hill
Ingrid Meulenbelt - Leiden University Medical Center
Christie M. Ballantyne - Houston Methodist
George V. Dedoussis - Harokopio University of Athens
Frank B. Hu - Harvard University
Yongmei Liu - Wake Forest University
Bernhard Paulweber - Paracelsus Medical University
Timothy D. Spector - King's College London
P. Eline Slagboom - Leiden University Medical Center
Luigi Ferrucci - National Institute on Aging
Antti Jula - Finnish Institute for Health and Welfare
Markus Perola - Institute for Molecular Medicine Finland
Olli Raitakari - University of Turku
Jose C. Florez - Massachusetts General Hospital
Veikko Salomaa - Finnish Institute for Health and Welfare
Johan G. Eriksson - Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Helsinki, Finland
Timothy M. Frayling - University of Exeter
Andrew A. Hicks - European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy
Terho Lehtimaki - University of Tampere
George Davey Smith - University of Bristol
David S. Siscovick
Florian Kronenberg - College Station Medical Center
Cornelia van Duijn - Erasmus MC
Ruth J. F. Loos - Massachusetts Rehabilitation Commission
Dawn M. Waterworth - GlaxoSmithKline
James B. Meigs - College Station Medical Center
Josee Dupuis - Boston University
J. Brent Richards - Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England
GLGC Investigators
Publication Details: PLoS genetics, Vol.8(3), pp.e1002607-e1002607
Publisher: Public Library Science
Number of pages: 23
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Genetics, Arthrosis, and Progression 114382; 213225; 216374; 129322; 125973; 210595 / Academy of Finland (AKA); Research Council of Finland Wellcome Trust R01-HL085251 / NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) TI-Pharma N01-HC-95172 / Tougaloo College Finnish Foundation of Cardiovascular Research Novo Nordisk Foundation; Novocure Limited U01HG004402 / National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) 114382; 126775; 127437; 129255; 129306; 130326; 209072; 210595; 213225; 216374; 126925; 121584; 124282; 129378; 117787; 41071; 125973; 129322; 129494; 139635; 129907; 135072 / Academy of Finland; Research Council of Finland National Institute of Neurological Disorders and Stroke; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Paavo Nurmi Foundation Finnish Cultural Foundation; Finnish IT center for science N02-HL-6-4278 / Affymetrix, Inc St Thomas' NHS Foundation Trust in partnership with King's College London Centre of Medical System Biology Sakari Sohlberg Foundation Finnish Foundation for Cardiovascular Research Arthritis Research Campaign, Chronic Disease Research Foundation Leiden University Medical Centre UL1RR025005 / a component of the National Institutes of Health and NIH Roadmap for Medical Research; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA "Austrian Genome Research Programme" (GEN-AU) DK063491; R01DK056918 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) G20234 / Biotechnology and Biological Sciences Research Council; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC) USA Ministere du Developpement economique Medizinische Forschungsgesellschaft Salzburg Samfundet Folkhalsan European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium MC_U127592696; G0601966; MC_U127561128; G0801056; MC_U137686857; G0700931; G0701863; G0902037; G0600705; MC_PC_U127592696; G0901213; MC_UP_A620_1015; MC_PC_U127561128; MC_UP_A100_1003; G0800582; G0900339 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine PENED 03; EPSILON; DELTA. 474 / General Secretary of Research and Technology M01-RR00425 / National Center for Research Resources; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Lady Davis Institute 118065 / Finnish Academy; Research Council of Finland Juho Vainio Foundation Orion-Farmos Research Foundation N01AG62101; N01AG62103; N01AG62106; 1R01AG032098-01A1 / NIA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
Identifiers: 9938807608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article