Genome‐wide Linkage and Association Analyses to Identify Genes Influencing Adiponectin Levels: The GEMS Stud |
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| Authors: | Hua Ling Dawn M Waterworth Heide A Stirnadel Toni I Pollin Philip J Barter Y Antero Kesäniemi Robert W Mahley Ruth McPherson Gérard Waeber Thomas P Bersot Jonathan C Cohen Scott M Grundy Vincent E Mooser Braxton D Mitchell |
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| Institution: | 1. Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, Maryland, USA;2. Medical Genetics/Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania, USA;3. World Wide Epidemiology, GlaxoSmithKline, Harlow, UK;4. Department of Medicine, University of Maryland, Baltimore, Maryland, USA;5. The Heart Research Institute, Sydney, New South Wales, Australia;6. Department of Internal Medicine, University of Oulu, Oulu, Finland;7. Biocenter Oulu, University of Oulu, Oulu, Finland;8. Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA;9. American Hospital, Istanbul, Turkey;10. Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada;11. Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland;12. Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA |
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| Abstract: | Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome‐wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome‐wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single‐nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10?7). These two SNPs were in high linkage disequilibrium (r2 = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 × 10?5) was to an SNP within CDH13, whose protein product is a newly identified receptor for high‐molecular‐weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined. |
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