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.
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D.J.L. is partially supported by R01HG008983 from the National Human Genome Research Institute of the National Institute of Health, and R21DA040177 and R01DA037904 from the National Institute of Drug Abuse of the National Institute of Health. G.M.P. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health award K01HL125751. A.P.P. is supported by a research fellowship from the Stanley J. Sarnoff Cardiovascular Research Foundation. H. Tada is supported by a grant from the Japanese Circulation Society to study in the United States. The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M.F. E.K.S. is supported by NIH grants R01 DK106621 and R01 DK107904, the University of Michigan Biological Sciences Scholars Program, and the University of Michigan Department of Internal Medicine. T.D.S. is supported by an ERC Advanced Principal Investigator award. A.P.M. is supported as a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant no. WT098017). Y.E.C. is supported by HL117491 and HL129778 from the NIH. S.K.G. is supported by HL122684 from the NIH. P.L.A. is supported by NHLBI R21 HL121422-02 from the NIH. C.L., N.J.W., and R.A.S. acknowledge funding from the Medical Research Council, UK (MC_UU_12015/1). J.D. is supported as a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. C.J.W. is supported by HL094535 and HL109946 from the NIH. S. Kathiresan is supported by a research scholar award from the Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564 and R33 HL120781 from the NIH.
The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health or the US Department of Health and Human Services.
This research has been conducted using the UK Biobank resource, application 7089. Funding support for participating studies in the meta-analysis can be found in the Supplementary Note.
Integrated supplementary information
Studies contributing to meta-analysis
Descriptive statistics for lipid levels across contributing studies.
Genotyping and analysis methods across contributing studies
Variant site distribution by alternative allele frequency and annotations
Forty new loci where non-protein-altering variants are associated with lipid levels
Reason for non-coding variants on array
Association results in current study for 175 previously reported GWAS variants
Association analysis of novel lipid loci in samples of European American, African American, South Asian, and Hispanic ancestries.
Gene-level association results
Replication results for 75 novel primary associations
Variance explained by known and independently associated SNPs
Association Results for 444 independently associated variants with lipid traits
Loci where protein-altering variant is top signal or protein-altering variant explains the GWAS signal
59 loci where there's a protein-altering variant that is either the top signal, explains the signal or is independent.
Association results for null mutations with p < 0.001
HDL-C variants and risk for age-related macular degeneration (AMD)
DNA variants in CETP robustly associate with HDL-C and risk for AMD
Thirty studies from populations of European ancestry contributing to PCSK9 p.R46L on risk of T2D
Association of LDL-C variants with coronary artery disease (CAD) and type 2 diabetes (T2D)
Definitions of outcomes in UK Biobank PheWAS
sgRNA sequences for functional follow-up experiments
About this article
Implications of publicly available genomic data resources in searching for therapeutic targets of obesity and type 2 diabetes
Experimental & Molecular Medicine (2018)