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Discovery and refinement of loci associated with lipid levels

Abstract

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

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Figure 1: Overlap of loci associated with different lipid traits.

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Acknowledgements

We especially thank the more than 196,000 volunteers who participated in our study. Detailed acknowledgment of funding sources is provided in the Supplementary Note.

Author information

Authors and Affiliations

Consortia

Contributions

Writing and analysis group: G.R.A., M. Boehnke, L.A.C., P.D., P.W.F., S. Kathiresan, K.L.M., E.I., G.M.P., S.S.R., S.R., M.S.S., E.M.S., S. Sengupta and C.J.W. (Lead). E.M.S. and S. Sengupta performed meta-analysis, and E.M.S., S. Sengupta, G.M.P., M.L.B., J.C., S.G., A.G. and S. Kanoni performed bioinformatics analyses. E.M.S. and S. Sengupta prepared the tables, figures and supplementary material. C.J.W. led the analysis and bioinformatics efforts. E.I. and K.L.M. led the biological interpretation of results. C.J.W. and G.R.A. wrote the manuscript. All analysis and writing group authors extensively discussed the analysis, results, interpretation and presentation of results.

All authors contributed to the research and reviewed the manuscript.

Design, management and coordination of contributing cohorts: (ADVANCE) T.L.A.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) D.K.S.; (AMC-PAS) P.D. and G.K.H.; (Amish GLGC) A.R.S.; (ARIC) E.B.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C.M.L., C. Power and M.I.M.; (BLSA) L.F.; (BRIGHT) P.B.M.; (CARDIOGRAM) N.S.; (CHS) B.M.P. and J.I.R.; (CLHNS) A.B.F., K.L.M. and L.S.A.; (CoLaus) P.V.; (CROATIA-Vis) C.H. and I.R.; (deCODE) K. Stefansson and U.T.; (DIAGEN) P.E.H.S. and S.R.B.; (DILGOM) S.R.; (DPS) M.U.; (DR's EXTRA) R.R.; (EAS) J.F.P.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (ELY) N.J.W.; (ENGAGE) N.B.F.; (EPIC) N.J.W. and K.-T.K.; (EPIC_N_OBSET GWAS) E.H.Y.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) P.J.K.; (Family Heart Study (FHS)) I.B.B.; (FBPP) A.C., R.S.C. and S.C.H.; (FENLAND) R.J.F.L. and N.J.W.; (FIN-D2D 27) A.K. and L.M.; (FINCAVAS) M. Kähönen; (Framingham) L.A.C., S. Kathiresan and J.M.O.; (FRISCII) A. Siegbahn and L.W.; (FUSION GWAS) K.L.M. and M. Boehnke; (FUSION stage 2) F.S.C., J.T. and J. Saramies; (GenomEUTwin) J.B.W., N.G.M., K.O.K., V.S., J. Kaprio, A.J., D.I.B., N.L.P. and T.D.S.; (GLACIER) P.W.F., G.H.; (Go-DARTS) A.D.M. and C.N.A.P.; (GxE/Spanish Town) B.O.T., C.A.M., F.B., J.N.H. and R.S.C.; (HUNT2) K. Hveem; (IMPROVE) U.d.F., A. Hamsten, E.T. and S.E.H.; (InCHIANTI) S.B.; (KORAF4) C.G.; (LifeLines) B.H.R.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) B.O.B. and W.M.; (MDC) L.C.G. and S. Kathiresan; (MEDSTAR) M.S.B., S.E.E.; (METSIM) J. Kuusisto and M.L.; (MICROS) P.P.P.; (MORGAM) D. Arveiler and J.F.; (MRC/UVRI GPC GWAS) P. Kaleebu, G.A., J. Seeley and E.H.Y.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) M.-R.J.; (NSPHS) U.G.; (ORCADES) H.C.; (PARC) Y.-D.I.C., R.M.K. and J.I.R.; (PennCath) D.J.R. and M.P.R.; (PIVUS) E.I. and L.L.; (PROMIS) J.D., P.D. and D. Saleheen; (Rotterdam Study) A. Hofman and A.G.U.; (SardiNIA) G.R.A.; (SCARFSHEEP) A. Hamsten and U.d.F.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (SUVIMAX) P.M.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) T.L.A., Y.-D.I.C., C.A.H., T.Q., J.I.R. and W.H.-H.S.; (THISEAS) G.D. and P.D.; (Tromsø) I.N.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; and (Whitehall II) A. Hingorani and M. Kivimaki.

Genotyping of contributing cohorts: (ADVANCE) D. Absher; (AIDHS/SDS) L.F.B. and M.L.G.; (AMC-PAS) P.D. and G.K.H.; (B58C-WTCCC and B58C-T1DGC) W.L.M.; (B58C-Metabochip) M.I.M.; (BLSA) D.H.; (BRIGHT) P.B.M.; (CHS) J.I.R.; (DIAGEN) N.N. and G.M.; (DILGOM) A. Palotie; (DR's EXTRA) T.A.L.; (EAS) J.F.W.; (EGCUT (Estonian Genome Center of the University of Tartu)) T.E.; (EPIC) P.D.; (EPIC_N_SUBCOH GWAS) I.B.; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) C.M.v.D.; (FBPP) A.C. and G.B.E.; (FENLAND) M.S.S.; (FIN-D2D 27) A.J.S.; (FINCAVAS) T.L.; (Framingham) J.M.O.; (FUSION stage 2) L.L.B.; (GLACIER) I.B.; (Go-DARTS) C.J.G., C.N.A.P. and M.I.M.; (IMPROVE) A. Hamsten; (KORAF3) H.G. and T.I.; (KORAF4) N.K.; (LifeLines) C.W.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) M.E.K.; (MDC) B.F.V. and R.D.; (MICROS) A.A.H.; (MORGAM) L.T. and P. Brambilla; (MRC/UVRI GPC GWAS) M.S.S.; (MRC National Survey of Health and Development) A.W., D.K. and K.K.O.; (NFBC1986) A.-L.H., M.-R.J., M.M., P.E. and S.V.; (NSPHS and FRISCII) Å.J.; (ORCADES) H.C.; (PARC) M.O.G., M.R.J. and J.I.R.; (PIVUS) E.I. and L.L.; (PROMIS) P.D. and K. Stirrups; (Rotterdam Study) A.G.U. and F.R.; (SardiNIA) R.N.; (SCARFSHEEP) B.G. and R.J.S.; (SEYCHELLES) F.M. and G.B.E.; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) D. Absher, T.L.A., E.K., T.Q. and L.L.W.; (THISEAS) P.D.; (TWINGENE) A. Hamsten and E.I.; (ULSAM) E.I.; (WGHS) D.I.C., S.M. and P.M.R.; and (Whitehall II) A. Hingorani, C.L., M. Kumari and M. Kivimaki.

Phenotype definition of contributing cohorts: (ADVANCE) C.I.; (AGES Reykjavik study) T.B.H. and V.G.; (AIDHS/SDS) L.F.B.; (AMC-PAS) J.J.P.K.; (Amish GLGC) A.R.S. and B.D.M.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (B58C-Metabochip) C. Power and E.H.; (BRIGHT) P.B.M.; (CHS) B.M.P.; (CoLaus) P.V.; (deCODE) G.I.E., H.H. and I.O.; (DIAGEN) G.M.; (DILGOM) K. Silander; (DPS) J. Lindström; (DR's EXTRA) P. Komulainen; (EAS) J.L.B.; (EGCUT (Estonian Genome Center of the University of Tartu)) A.M.; (EGCUT (Estonian Genome Center of the University of Tartu)) K.F.; (ERF and Rotterdam Study) A. Hofman; (ERF) C.M.v.D.; (ESS (Erasmus Stroke Study)) E.G.V.d.H., H.M.D.H. and P.J.K.; (FBPP) A.C., R.S.C. and S.C.H.; (FINCAVAS) T.V.M.N.; (Framingham) S. Kathiresan and J.M.O.; (GenomEUTwin: MZGWA) J.B.W.; (GenomEUTwin-FINRISK) V.S.; (GenomEUTwin-FINTWIN) J. Kaprio and K. Heikkilä; (GenomEUTwin-GENMETS) A.J.; (GenomEUTwin-NLDTWIN) G.W.; (Go-DARTS) A.S.F.D., A.D.M., C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.A.M. and F.B.; (IMPROVE) U.d.F., A. Hamsten and E.T.; (KORAF3) C.M.; (KORAF4) A. Döring; (LifeLines) L.J.v.P.; (LOLIPOP) J.S.K. and J.C.C.; (LURIC) H.S.; (MDC) L.C.G.; (METSIM) A. Stančáková; (MORGAM) G.C.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) D.K.; (NFBC1986) A.R., A.-L.H., A. Pouta and M.-R.J.; (NSPHS and FRISCII) Å.J.; (NSPHS) U.G.; (ORCADES) S.H.W.; (PARC) Y.-D.I.C. and R.M.K.; (PIVUS) E.I. and L.L.; (PROMIS) D.F.F.; (Rotterdam Study) A. Hofman; (SCARFSHEEP) U.d.F. and B.G.; (SEYCHELLES) M. Burnier, M. Bochud and P. Bovet; (Swedish Twin Registry) E.I. and N.L.P.; (TAICHI) H.-Y.C., C.A.H., Y.-J.H., E.K., S.-Y.L. and W.H.-H.S.; (THISEAS) G.D. and M.D.; (Tromsø) T.W.; (TWINGENE) U.d.F. and E.I.; (ULSAM) E.I.; (WGHS) P.M.R.; and (Whitehall II) M. Kumari.

Primary analysis from contributing cohorts: (ADVANCE) L.L.W.; (AIDHS/SDS) R.S.; (AMC-PAS) S. Kanoni; (Amish GLGC) J.R.O. and M.E.M.; (ARIC) K.A.V.; (B58C-Metabochip) C.M.L., E.H. and T.F.; (B58C-WTCCC and B58C-T1DGC) D.P.S.; (BLSA) T.T.; (BRIGHT) T.J.; (CLHNS) Y.W.; (CoLaus) J.S.B.; (deCODE) G.T.; (DIAGEN) A.U.J.; (DILGOM) M.P.; (EAS) R.M.F.; (DPS) A.U.J.; (DR's EXTRA) A.U.J.; (EGCUT (Estonian Genome Center of the University of Tartu)) E.M., K.F. and T.E.; (ELY) D.G.; (EPIC) K. Stirrups and D.G.; (EPIC_N_OBSET GWAS) E.H.Y. and C.L.; (EPIC_N_SUBCOH GWAS) N.W.; (ERF) A.I.; (ESS (Erasmus Stroke Study)) C.M.v.D. and E.G.V.d.H.; (EUROSPAN) A. Demirkan; (Family Heart Study (FHS)) I.B.B. and M.F.F.; (FBPP) A.C. and G.B.E.; (FENLAND) T.P. and C. Pomilla; (FENLAND GWAS) J.H.Z. and J. Luan; (FIN-D2D 27) A.U.J.; (FINCAVAS) L.-P.L.; (Framingham) L.A.C. and G.M.P.; (FRISCII and NSPHS) Å.J.; (FUSION stage 2) T.M.T.; (GenomEUTwin-FINRISK) J. Kettunen; (GenomEUTwin-FINTWIN) K. Heikkilä; (GenomEUTwin-GENMETS) I.S.; (GenomEUTwin-SWETWIN) P.K.E.M.; (GenomEUTwin-UK-TWINS) M.M.; (GLACIER) D. Shungin; (GLACIER) P.W.F.; (Go-DARTS) C.N.A.P. and L.A.D.; (GxE/Spanish Town) C.D.P.; (HUNT) A.U.J.; (IMPROVE) R.J.S.; (InCHIANTI) T.T.; (KORAF3) M.M.-N.; (KORAF4) A.-K.P.; (LifeLines) I.M.N.; (LOLIPOP) W.Z.; (LURIC) M.E.K.; (MDC) B.F.V.; (MDC) P.F. and R.D.; (METSIM) A.U.J.; (MRC/UVRI GPC GWAS) R.N.N.; (MRC National Survey of Health and Development) A.W. and J. Luan; (NFBC1986) M. Kaakinen, I.S. and S.K.S.; (NSPHS and FRISCII) Å.J.; (PARC) X.L.; (PIVUS) C. Song and E.I.; (PROMIS) J.D., D.F.F. and K. Stirrups; (Rotterdam Study) A.I.; (SardiNIA) C. Sidore, J.L.B.-G. and S. Sanna; (SCARFSHEEP) R.J.S.; (SEYCHELLES) G.B.E. and M. Bochud; (SUVIMAX) T.J.; (Swedish Twin Registry) C. Song and E.I.; (TAICHI) D. Absher, T.L.A., H.-Y.C., M.O.G., C.A.H., T.Q. and L.L.W.; (THISEAS) S. Kanoni; (Tromsø) A.U.J.; (TWINGENE) A.G. and E.I.; (ULSAM) C. Song, E.I. and S.G.; (WGHS) D.I.C.; and (Whitehall II) S. Shah.

Corresponding authors

Correspondence to Cristen J Willer, Karen L Mohlke, Erik Ingelsson or Gonçalo R Abecasis.

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Competing interests

B.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the manufacturer (Zoll), and he serves on the Steering Committee of the Yale Open-Data Project funded by the Medtronic. P.V. received an unrestricted grant from GlaxoSmithKline to build the CoLaus study. G.T., H.H., A.K., K. Stefansson and U.T. are employees of deCODE Genetics/Amgen, a biotechnology company. I.B. and spouse own stock in GlaxoSmithKline and Incyte, Ltd.

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Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet 45, 1274–1283 (2013). https://doi.org/10.1038/ng.2797

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