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.

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Background-Dyslipidemias are the major cause for atherosclerosis. They may act synergistically with nonlipid risk factors to increase atherogenesis. In the present study, we examined the effects of dyslipidemias from childhood to adulthood and their interaction with nonlipid risk factors on markers of subclinical atherosclerosis. Methods and Results-Study subjects were participants of the longitudinal Cardiovascular Risk in Young Finns Study started in 1980 (nϭ2265, age 3 to 18 years). To phenotype type IIa, IIb, and IV dyslipidemias and hypoHDL-cholesterolemia, we calculated age and sex-specific z scores for lipid values for each subject in 1980, 1983, 1986, and 2001. Subjects with mean z score over 90th percentile for LDL-cholesterol or triglycerides were considered having type IIa or IV dyslipidemia. Subjects with mean z score over 90th percentile for LDL-cholesterol and triglycerides had type IIb dyslipidemia, and those with mean z score below 10th percentile for HDL-cholesterol had hypoHDL-cholesterolemia.