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

• Authors: Peter W Wilson, Emory University
• Journal Title: Nature Genetics
• Volume: Volume 49, Number 12
• Publisher: Nature Publishing Group | 2017-12-01, Pages 1758-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/ng.3977
• Subjects: Health Sciences, General; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; APOBEC-1 COMPLEMENTATION FACTOR; CODING-SEQUENCE VARIANTS; TYROSINE KINASE JAK2; B MESSENGER-RNA; MACULAR DEGENERATION; GENETIC ARCHITECTURE; LOW-FREQUENCY; MYELOPROLIFERATIVE DISORDERS; CARDIOVASCULAR-DISEASE; CLONAL HEMATOPOIESIS

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-densitylipoprotein 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 TGrich 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.