Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Am J Hum Genet. 2019 Jul 3;105(1):15-28. doi: 10.1016/j.ajhg.2019.05.002. Epub 2019 Jun 6.

Abstract

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Keywords: adiponectin; cardio metabolic traits; exome; genetics; genome-wide association study; lipids; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / genetics*
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology*
  • Adolescent
  • Adult
  • African Americans / genetics
  • Aged
  • Aged, 80 and over
  • European Continental Ancestry Group / genetics
  • Exome / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Hispanic Americans / genetics
  • Humans
  • Lipids / analysis*
  • Male
  • Middle Aged
  • Obesity / etiology*
  • Obesity / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci
  • Young Adult

Substances

  • ADIPOQ protein, human
  • Adiponectin
  • Lipids