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 = 4.561028
–
1.2610243). 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,361024
). 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 = 4.361023
, n = 22,044), increased triglycerides (p = 2.6610214,
n = 93,440), increased waist-to-hip ratio (p = 1.861025
, n = 77,167), increased glucose two hours post oral glucose
tolerance testing (p = 4.461023
, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDLcholesterol
concentrations (p = 4.5610213, n = 96,748) and decreased BMI (p = 1.461024
, n = 121,335). These findings
identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of
insulin resistance.