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

Dajiang J. Liu; Gina M. Peloso; Haojie Yu; Adam S. Butterworth; Xiao-Yu Wang; Anubha Mahajan; Danish Saleheen; Connor Emdin; Dewan S. Alam; Alexessander Couto Alves; Philippe Amouyel; Emanuele Di Angelantonio; Dominique Arveiler; Themistocles L. Assimes; Paul L. Auer; Usman Baber; Christie M. Ballantyne; Lia E. Bang; Marianne Benn; Joshua C. Bis; Michael Boehnke; Eric Boerwinkle; Jette Bork-Jensen; Erwin P. Bottinger; Ivan Brandslund; Morris J. Brown; Fabio Busonero; Mark J. Caulfield; John C. Chambers; Daniel I. Chasman; Y Eugene Chen; Yii-Der Ida Chen; Rajiv Chowdhury; Cramer Christensen; Audrey Y. Chu; John M. Connell; Francesco Cucca; L. Adrienne Cupples; Scott M Damrauer; Gail Davies; Ian J. Deary; George Dedoussis; Joshua C. Denny; Anna F. Dominiczak; Marie Pierre  Dubé; Tapani Ebeling; Gudny Eiriksdottir; Tõnu Esko; Colin N. A. Palmer; Blair H. Smith; Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium,	GOLD Consortium, VA Million Veteran Program; Sekar Kathiresan; Cristen J. Willer

doi:10.1038/ng.3977

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

Dajiang J. Liu, Gina M. Peloso, Haojie Yu, Adam S. Butterworth, Xiao-Yu Wang, Anubha Mahajan, Danish Saleheen, Connor Emdin, Dewan S. Alam, Alexessander Couto Alves, Philippe Amouyel, Emanuele Di Angelantonio, Dominique Arveiler, Themistocles L. Assimes, Paul L. Auer, Usman Baber, Christie M. Ballantyne, Lia E. Bang, Marianne Benn, Joshua C. BisMichael Boehnke, Eric Boerwinkle, Jette Bork-Jensen, Erwin P. Bottinger, Ivan Brandslund, Morris J. Brown, Fabio Busonero, Mark J. Caulfield, John C. Chambers, Daniel I. Chasman, Y Eugene Chen, Yii-Der Ida Chen, Rajiv Chowdhury, Cramer Christensen, Audrey Y. Chu, John M. Connell, Francesco Cucca, L. Adrienne Cupples, Scott M Damrauer, Gail Davies, Ian J. Deary, George Dedoussis, Joshua C. Denny, Anna F. Dominiczak, Marie Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Colin N. A. Palmer, Blair H. Smith, Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program, Sekar Kathiresan (Lead / Corresponding author), Cristen J. Willer (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	1758-1766
Number of pages	9
Journal	Nature Genetics
Volume	49
Issue number	12
Early online date	30 Oct 2017
DOIs	https://doi.org/10.1038/ng.3977
Publication status	Published - 30 Oct 2017

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3977

Author Accepted ManuscriptAccepted author manuscript, 1.07 MB

Smith, Blair, FRSE MD MEd FRCGP FFPMRCA FRCP Edin
- Population Health and Genomics - Clinical Professor (Teaching and Research) of Population Health Science
Person: Academic

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Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X.-Y., Mahajan, A., Saleheen, D., Emdin, C., Alam, D. S., Alves, A. C., Amouyel, P., Di Angelantonio, E., Arveiler, D., Assimes, T. L., Auer, P. L., Baber, U., Ballantyne, C. M., Bang, L. E., Benn, M., ... Willer, C. J. (2017). Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49(12), 1758-1766. https://doi.org/10.1038/ng.3977

@article{38cb0d27258644bd8844d146487b3845,

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

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.",

author = "Liu, {Dajiang J.} and Peloso, {Gina M.} and Haojie Yu and Butterworth, {Adam S.} and Xiao-Yu Wang and Anubha Mahajan and Danish Saleheen and Connor Emdin and Alam, {Dewan S.} and Alves, {Alexessander Couto} and Philippe Amouyel and {Di Angelantonio}, Emanuele and Dominique Arveiler and Assimes, {Themistocles L.} and Auer, {Paul L.} and Usman Baber and Ballantyne, {Christie M.} and Bang, {Lia E.} and Marianne Benn and Bis, {Joshua C.} and Michael Boehnke and Eric Boerwinkle and Jette Bork-Jensen and Bottinger, {Erwin P.} and Ivan Brandslund and Brown, {Morris J.} and Fabio Busonero and Caulfield, {Mark J.} and Chambers, {John C.} and Chasman, {Daniel I.} and Chen, {Y Eugene} and Chen, {Yii-Der Ida} and Rajiv Chowdhury and Cramer Christensen and Chu, {Audrey Y.} and Connell, {John M.} and Francesco Cucca and Cupples, {L. Adrienne} and Damrauer, {Scott M} and Gail Davies and Deary, {Ian J.} and George Dedoussis and Denny, {Joshua C.} and Dominiczak, {Anna F.} and Dub{\'e}, {Marie Pierre} and Tapani Ebeling and Gudny Eiriksdottir and T{\~o}nu Esko and Palmer, {Colin N. A.} and Smith, {Blair H.} and {Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program} and Sekar Kathiresan and Willer, {Cristen J.}",

note = "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.",

year = "2017",

month = oct,

day = "30",

doi = "10.1038/ng.3977",

language = "English",

volume = "49",

pages = "1758--1766",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Liu, DJ, Peloso, GM, Yu, H, Butterworth, AS, Wang, X-Y, Mahajan, A, Saleheen, D, Emdin, C, Alam, DS, Alves, AC, Amouyel, P, Di Angelantonio, E, Arveiler, D, Assimes, TL, Auer, PL, Baber, U, Ballantyne, CM, Bang, LE, Benn, M, Bis, JC, Boehnke, M, Boerwinkle, E, Bork-Jensen, J, Bottinger, EP, Brandslund, I, Brown, MJ, Busonero, F, Caulfield, MJ, Chambers, JC, Chasman, DI, Chen, YE, Chen, Y-DI, Chowdhury, R, Christensen, C, Chu, AY, Connell, JM, Cucca, F, Cupples, LA, Damrauer, SM, Davies, G, Deary, IJ, Dedoussis, G, Denny, JC, Dominiczak, AF, Dubé, MP, Ebeling, T, Eiriksdottir, G, Esko, T, Palmer, CNA , Smith, BH, Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program, Kathiresan, S & Willer, CJ 2017, 'Exome-wide association study of plasma lipids in >300,000 individuals', Nature Genetics, vol. 49, no. 12, pp. 1758-1766. https://doi.org/10.1038/ng.3977

TY - JOUR

T1 - Exome-wide association study of plasma lipids in >300,000 individuals

AU - Liu, Dajiang J.

AU - Peloso, Gina M.

AU - Yu, Haojie

AU - Butterworth, Adam S.

AU - Wang, Xiao-Yu

AU - Mahajan, Anubha

AU - Saleheen, Danish

AU - Emdin, Connor

AU - Alam, Dewan S.

AU - Alves, Alexessander Couto

AU - Amouyel, Philippe

AU - Di Angelantonio, Emanuele

AU - Arveiler, Dominique

AU - Assimes, Themistocles L.

AU - Auer, Paul L.

AU - Baber, Usman

AU - Ballantyne, Christie M.

AU - Bang, Lia E.

AU - Benn, Marianne

AU - Bis, Joshua C.

AU - Boehnke, Michael

AU - Boerwinkle, Eric

AU - Bork-Jensen, Jette

AU - Bottinger, Erwin P.

AU - Brandslund, Ivan

AU - Brown, Morris J.

AU - Busonero, Fabio

AU - Caulfield, Mark J.

AU - Chambers, John C.

AU - Chasman, Daniel I.

AU - Chen, Y Eugene

AU - Chen, Yii-Der Ida

AU - Chowdhury, Rajiv

AU - Christensen, Cramer

AU - Chu, Audrey Y.

AU - Connell, John M.

AU - Cucca, Francesco

AU - Cupples, L. Adrienne

AU - Damrauer, Scott M

AU - Davies, Gail

AU - Deary, Ian J.

AU - Dedoussis, George

AU - Denny, Joshua C.

AU - Dominiczak, Anna F.

AU - Dubé, Marie Pierre

AU - Ebeling, Tapani

AU - Eiriksdottir, Gudny

AU - Esko, Tõnu

AU - Palmer, Colin N. A.

AU - Smith, Blair H.

AU - Charge Diabetes Working Group, The EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program

AU - Kathiresan, Sekar

AU - Willer, Cristen J.

N1 - 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.

PY - 2017/10/30

Y1 - 2017/10/30

N2 - 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.

AB - 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.

U2 - 10.1038/ng.3977

DO - 10.1038/ng.3977

M3 - Letter

C2 - 29083408

SN - 1061-4036

VL - 49

SP - 1758

EP - 1766

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

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

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UN SDGs

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Smith, Blair, FRSE MD MEd FRCGP FFPMRCA FRCP Edin

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