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The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10 −8 ). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding  ADIPOQ  locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10 −19  for lead SNP, rs266717, n = 14,733). A novel variant in the  ARL15  (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10 −8 , n = 14,733). This same risk allele at  ARL15  was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10 −6 , n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10 −3 , n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels