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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Dastani, Zari 
Hivert, Marie-France 
Timpson, Nicholas 
Perry, John RB 
Yuan, Xin 

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 = 4.5×10(-8)-1.2×10(-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<3×10(-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 = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Adiponectin, Black or African American, Asian People, Cholesterol, HDL, Diabetes Mellitus, Type 2, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, White People
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PLoS Genet
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Public Library of Science (PLoS)
Medical Research Council (G0401527)
Medical Research Council (G0901213)
Medical Research Council (G1000143)
Medical Research Council (MR/K013491/1)
British Heart Foundation (None)
Medical Research Council (G0701863)
Medical Research Council (MC_UU_12015/1)
Medical Research Council (G0600717)
Medical Research Council (MC_U106179471)
Wellcome Trust (092447/Z/10/Z)