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 & 31 andre 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, Torben Hansen, Gorm B Jensen, Marit E Jørgensen, Charge Diabetes Working Group

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Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind49
Sider (fra-til)1758–1766
ISSN1061-4036
DOI
StatusUdgivet - 2017

Fingeraftryk

Exome
Lipids
Type 2 Diabetes Mellitus
Coronary Artery Disease
LDL Cholesterol
HDL Cholesterol
Liver
Fats
Alleles
beta-Thalassemia
Macular Degeneration
Lipoproteins

Citer dette

Liu, D. J., Peloso, G. M., Yu, H., Butterworth, A. S., Wang, X., Mahajan, A., ... Charge Diabetes Working Group (2017). Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics, 49, 1758–1766. https://doi.org/10.1038/ng.3977
Liu, Dajiang J ; Peloso, Gina M ; Yu, Haojie ; Butterworth, Adam S ; Wang, Xiao ; Mahajan, Anubha ; Saleheen, Danish ; Emdin, Connor ; Alam, Dewan ; Alves, Alexessander Couto ; Amouyel, Philippe ; Di Angelantonio, Emanuele ; Arveiler, Dominique ; Assimes, Themistocles L ; Auer, Paul L ; Baber, Usman ; Ballantyne, Christie M ; Bang, Lia E ; Benn, Marianne ; Bis, Joshua C ; Boehnke, Michael ; Boerwinkle, Eric ; Bork-Jensen, Jette ; Bottinger, Erwin P ; Brandslund, Ivan ; Brown, Morris ; Busonero, Fabio ; Caulfield, Mark J ; Chambers, John C ; Chasman, Daniel I ; Chen, Y Eugene ; Chen, Yii-Der Ida ; Chowdhury, Rajiv ; Christensen, Cramer ; Chu, Audrey Y ; Connell, John M ; Cucca, Francesco ; Cupples, L Adrienne ; Damrauer, Scott M ; Davies, Gail ; Deary, Ian J ; Dedoussis, George ; Denny, Joshua C ; Dominiczak, Anna ; Dubé, Marie-Pierre ; Ebeling, Tapani ; Eiriksdottir, Gudny ; Hansen, Torben ; Jensen, Gorm B ; Jørgensen, Marit E ; Charge Diabetes Working Group. / Exome-wide association study of plasma lipids in >300,000 individuals. I: Nature Genetics. 2017 ; Bind 49. s. 1758–1766.
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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.",
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 Torben Hansen and Jensen, {Gorm B} and J{\o}rgensen, {Marit E} and {Charge Diabetes Working Group}",
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pages = "1758–1766",
journal = "Nature Genetics",
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publisher = "Nature Publishing Group",

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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, Hansen, T, Jensen, GB, Jørgensen, ME & Charge Diabetes Working Group 2017, 'Exome-wide association study of plasma lipids in >300,000 individuals', Nature Genetics, bind 49, s. 1758–1766. https://doi.org/10.1038/ng.3977

Exome-wide association study of plasma lipids in >300,000 individuals. / Liu, Dajiang J; Peloso, Gina M; Yu, Haojie; Butterworth, Adam S; Wang, Xiao; Mahajan, Anubha; Saleheen, Danish; Emdin, Connor; Alam, Dewan; Alves, Alexessander Couto; Amouyel, Philippe; Di Angelantonio, Emanuele; Arveiler, Dominique; Assimes, Themistocles L; Auer, Paul L; Baber, Usman; Ballantyne, Christie M; Bang, Lia E; Benn, Marianne; Bis, Joshua C; Boehnke, Michael; Boerwinkle, Eric; Bork-Jensen, Jette; Bottinger, Erwin P; Brandslund, Ivan; Brown, Morris; Busonero, Fabio; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Y Eugene; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Connell, John M; Cucca, Francesco; Cupples, L Adrienne; Damrauer, Scott M; Davies, Gail; Deary, Ian J; Dedoussis, George; Denny, Joshua C; Dominiczak, Anna; Dubé, Marie-Pierre; Ebeling, Tapani; Eiriksdottir, Gudny; Hansen, Torben; Jensen, Gorm B; Jørgensen, Marit E; Charge Diabetes Working Group.

I: Nature Genetics, Bind 49, 2017, s. 1758–1766.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - Hansen, Torben

AU - Jensen, Gorm B

AU - Jørgensen, Marit E

AU - Charge Diabetes Working Group

PY - 2017

Y1 - 2017

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 - Journal article

VL - 49

SP - 1758

EP - 1766

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nature Genetics. 2017;49:1758–1766. https://doi.org/10.1038/ng.3977