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

Dajiang J Liu; Gina M Peloso; Haojie Yu; Adam S Butterworth; Xiao Wang; Anubha Mahajan; Danish Saleheen; Connor Emdin; Dewan 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 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 Dominiczak; Marie-Pierre Dubé; Tapani Ebeling; Gudny Eiriksdottir; Serena Sanna; Albert V Smith; Yan Zhang; Charge Diabetes Working Group

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 Wang
, Anubha Mahajan
, Danish Saleheen
, Connor Emdin
, Dewan 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 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 Dominiczak, Marie-Pierre Dubé, Tapani Ebeling, Gudny Eiriksdottir, Serena Sanna, Albert V Smith, Yan Zhang, Charge Diabetes Working Group

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Research output: Contribution to journal › Letter (Research letter) › Academic › peer-review

459 Citations (Scopus)

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	14
Journal	Nature Genetics
Volume	49
Issue number	12
DOIs	https://doi.org/10.1038/ng.3977
Publication status	Published - Dec-2017

Keywords

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
Journal Article

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Exome-wide association study of plasma lipids in >300,000 individuals
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Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X., Mahajan, A., Saleheen, D., Emdin, C., Alam, D., 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., ... Charge Diabetes Working Group (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{485f2ba729024caaba67f10f866bad6d,

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.",

keywords = "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, Journal Article",

author = "Liu, \{Dajiang J\} and Peloso, \{Gina M\} and Haojie Yu and Butterworth, \{Adam S\} and Xiao Wang and Anubha Mahajan and Danish Saleheen and Connor Emdin and Dewan Alam 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 Morris Brown 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 Anna Dominiczak and Marie-Pierre Dub{\'e} and Tapani Ebeling and Gudny Eiriksdottir and Serena Sanna and Smith, \{Albert V\} and Yan Zhang and \{Charge Diabetes Working Group\}",

year = "2017",

month = dec,

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, Mahajan, A, Saleheen, D, Emdin, C, Alam, D, 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, M, 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, A, Dubé, M-P, Ebeling, T, Eiriksdottir, G, Sanna, S, Smith, AV, Zhang, Y & Charge Diabetes Working Group 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

AU - Mahajan, Anubha

AU - Saleheen, Danish

AU - Emdin, Connor

AU - Alam, Dewan

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

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

AU - Dubé, Marie-Pierre

AU - Ebeling, Tapani

AU - Eiriksdottir, Gudny

AU - Sanna, Serena

AU - Smith, Albert V

AU - Zhang, Yan

AU - Charge Diabetes Working Group

PY - 2017/12

Y1 - 2017/12

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.

KW - Coronary Artery Disease

KW - Diabetes Mellitus, Type 2

KW - Exome

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genotype

KW - Humans

KW - Lipids

KW - Macular Degeneration

KW - Phenotype

KW - Risk Factors

KW - Journal Article

U2 - 10.1038/ng.3977

DO - 10.1038/ng.3977

M3 - Letter (Research 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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Keywords

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