Exome-wide association study of plasma lipids in >300,000 individuals

Nat Genet. 2017 Dec;49(12):1758-1766. doi: 10.1038/ng.3977. Epub 2017 Oct 30.

Abstract

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

MeSH terms

  • Coronary Artery Disease / blood
  • Coronary Artery Disease / genetics
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics
  • Exome / genetics*
  • Genetic Association Studies / methods*
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation*
  • Genotype
  • Humans
  • Lipids / blood*
  • Macular Degeneration / blood
  • Macular Degeneration / genetics
  • Phenotype
  • Risk Factors

Substances

  • Lipids

Grant support