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

TitleExome-wide association study of plasma lipids in >300,000 individuals.
Publication TypeJournal Article
Year of Publication2017
AuthorsLiu DJ, Peloso GM, Yu H, et al.
Secondary AuthorsKathiresan S
Corporate AuthorsCharge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program
JournalNat Genet
Volume49
Issue12
Pagination1758-1766
Date Published2017 Dec
ISSN1546-1718
KeywordsCoronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Lipids, Macular Degeneration, Phenotype, Risk Factors
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.

DOI10.1038/ng.3977
Alternate JournalNat Genet
PubMed ID29083408
PubMed Central IDPMC5709146
Grant ListR01 DK106621 / DK / NIDDK NIH HHS / United States
R01 HL109946 / HL / NHLBI NIH HHS / United States
R01 HL118567 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom
U54 GM115428 / GM / NIGMS NIH HHS / United States
R21 HL121422 / HL / NHLBI NIH HHS / United States
KL2 TR001100 / TR / NCATS NIH HHS / United States
G9521010 / MRC_ / Medical Research Council / United Kingdom
R01 HL122684 / HL / NHLBI NIH HHS / United States
MR/P013880/1 / MRC_ / Medical Research Council / United Kingdom
R21 DA040177 / DA / NIDA NIH HHS / United States
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
T32 HG000040 / HG / NHGRI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
MC_PC_14089 / MRC_ / Medical Research Council / United Kingdom
MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL117491 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
S10 OD018522 / OD / NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL129778 / HL / NHLBI NIH HHS / United States
K99 HL094535 / HL / NHLBI NIH HHS / United States
K01 HL125751 / HL / NHLBI NIH HHS / United States
MR/N005813/1 / MRC_ / Medical Research Council / United Kingdom
R01 HG008983 / HG / NHGRI NIH HHS / United States
MC_EX_MR/M009203/1 / MRC_ / Medical Research Council / United Kingdom
K24 DK080140 / DK / NIDDK NIH HHS / United States
R00 HL094535 / HL / NHLBI NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
MR/P02811X/1 / MRC_ / Medical Research Council / United Kingdom
U01 DK078616 / DK / NIDDK NIH HHS / United States
R01 DA037904 / DA / NIDA NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
G0601261 / MRC_ / Medical Research Council / United Kingdom
G0600237 / MRC_ / Medical Research Council / United Kingdom