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

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

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.

Coronary Artery Disease/blood, Diabetes Mellitus, Type 2/blood, Exome/genetics, Genetic Association Studies/methods, Genetic Predisposition to Disease/genetics, Genetic Variation, Genotype, Humans, Lipids/blood, Macular Degeneration/blood, Phenotype, Risk Factors
1061-4036
1758-1766
Liu, Dajiang J
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Peloso, Gina M
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Yu, Haojie
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Butterworth, Adam S
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Wang, Xiao
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Mahajan, Anubha
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Saleheen, Danish
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Emdin, Connor
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Alam, Dewan
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Alves, Alexessander Couto
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Amouyel, Philippe
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Di Angelantonio, Emanuele
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Arveiler, Dominique
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Assimes, Themistocles L
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Auer, Paul L
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Ballantyne, Christie M
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Bang, Lia E
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Benn, Marianne
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Bis, Joshua C
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Boerwinkle, Eric
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Bottinger, Erwin P
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Brandslund, Ivan
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Brown, Morris
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Busonero, Fabio
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Caulfield, Mark J
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Chambers, John C
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Chasman, Daniel I
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Chen, Y Eugene
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Chen, Yii-Der Ida
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Chowdhury, Rajiv
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Christensen, Cramer
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Chu, Audrey Y
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Damrauer, Scott M
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Zhang, Yan
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Charge Diabetes Working Group
Liu, Dajiang J
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Peloso, Gina M
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Yu, Haojie
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Butterworth, Adam S
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Wang, Xiao
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Mahajan, Anubha
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Saleheen, Danish
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Emdin, Connor
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Alam, Dewan
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Alves, Alexessander Couto
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Amouyel, Philippe
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Di Angelantonio, Emanuele
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Arveiler, Dominique
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Assimes, Themistocles L
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Auer, Paul L
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Baber, Usman
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Bang, Lia E
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Boehnke, Michael
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Boerwinkle, Eric
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Brandslund, Ivan
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Brown, Morris
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Busonero, Fabio
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Caulfield, Mark J
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Chasman, Daniel I
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Chen, Y Eugene
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Chen, Yii-Der Ida
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Chowdhury, Rajiv
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Christensen, Cramer
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Chu, Audrey Y
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Connell, John M
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Cucca, Francesco
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Cupples, L Adrienne
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Damrauer, Scott M
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Dominiczak, Anna
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Dubé, Marie-Pierre
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Ebeling, Tapani
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Wilson, James G
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Wilson, Peter W F
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Zhang, Yan
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Charge Diabetes Working Group (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49 (12), 1758-1766. (doi:10.1038/ng.3977).

Record type: 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.

This record has no associated files available for download.

More information

Published date: 1 December 2017
Keywords: Coronary Artery Disease/blood, Diabetes Mellitus, Type 2/blood, Exome/genetics, Genetic Association Studies/methods, Genetic Predisposition to Disease/genetics, Genetic Variation, Genotype, Humans, Lipids/blood, Macular Degeneration/blood, Phenotype, Risk Factors

Identifiers

Local EPrints ID: 494180
URI: http://eprints.soton.ac.uk/id/eprint/494180
DOI: doi:10.1038/ng.3977
ISSN: 1061-4036
PURE UUID: f65d89bd-8d89-42e5-a426-78ea9279e49d
ORCID for Alexessander Couto Alves: ORCID iD orcid.org/0000-0001-8519-7356
ORCID for Yan Zhang: ORCID iD orcid.org/0000-0003-3470-3663

Catalogue record

Date deposited: 26 Sep 2024 16:50
Last modified: 26 Oct 2024 02:12

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Contributors

Author: Dajiang J Liu
Author: Gina M Peloso
Author: Haojie Yu
Author: Adam S Butterworth
Author: Xiao Wang
Author: Anubha Mahajan
Author: Danish Saleheen
Author: Connor Emdin
Author: Dewan Alam
Author: Alexessander Couto Alves ORCID iD
Author: Philippe Amouyel
Author: Emanuele Di Angelantonio
Author: Dominique Arveiler
Author: Themistocles L Assimes
Author: Paul L Auer
Author: Usman Baber
Author: Christie M Ballantyne
Author: Lia E Bang
Author: Marianne Benn
Author: Joshua C Bis
Author: Michael Boehnke
Author: Eric Boerwinkle
Author: Jette Bork-Jensen
Author: Erwin P Bottinger
Author: Ivan Brandslund
Author: Morris Brown
Author: Fabio Busonero
Author: Mark J Caulfield
Author: John C Chambers
Author: Daniel I Chasman
Author: Y Eugene Chen
Author: Yii-Der Ida Chen
Author: Rajiv Chowdhury
Author: Cramer Christensen
Author: Audrey Y Chu
Author: John M Connell
Author: Francesco Cucca
Author: L Adrienne Cupples
Author: Scott M Damrauer
Author: Gail Davies
Author: Ian J Deary
Author: George Dedoussis
Author: Joshua C Denny
Author: Anna Dominiczak
Author: Marie-Pierre Dubé
Author: Tapani Ebeling
Author: Colin N A Palmer
Author: James G Wilson
Author: Peter W F Wilson
Author: Yan Zhang ORCID iD
Corporate Author: Charge Diabetes Working Group

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