Exome-wide association study of plasma lipids in >300,000 individuals.
File(s)
Supporting information
Author(s)
Type
Journal Article
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.
Date Issued
2017-10-30
Date Acceptance
2017-09-26
Citation
Nature Genetics, 2017, 49, pp.1758-1766
ISSN
1061-4036
Publisher
Nature Publishing Group
Start Page
1758
End Page
1766
Journal / Book Title
Nature Genetics
Volume
49
Copyright Statement
Copyright © 2017, Rights Managed by Nature Publishing Group
Identifier
PII: ng.3977
Subjects
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
Coronary Artery Disease
Diabetes Mellitus, Type 2
Exome
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genotype
Humans
Lipids
Macular Degeneration
Phenotype
Risk Factors
Charge Diabetes Working Group
EPIC-InterAct Consortium
EPIC-CVD Consortium
GOLD Consortium
VA Million Veteran Program
11 Medical And Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status
Published online