Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Abbas Dehghan; Joshua C. Bis; Charles C. White; Albert Vernon Smith; Alanna C. Morrison; L. Adrienne Cupples; Stella Trompet; Daniel I. Chasman; Thomas Lumley; Uwe Volker; Brendan M. Buckley; Jingzhong Ding; Majken K. Jensen; Aaron R. Folsom; Stephen B. Kritchevsky; Cynthia J. Girman; Ian Ford; Marcus Dorr; Veikko Salomaa; Andre G. Uitterlinden; Gudny Eiriksdottir; Ramachandran S. Vasan; Nora Franceschini; Cara L. Carty; Jarmo Virtamo; Serkalem Demissie; Philippe Amouyel; Dominique Arveiler; Susan R. Heckbert; Jean Ferrieres; Pierre Ducimetiere; Nicholas L. Smith; Ying A. Wang; David S. Siscovick; Kenneth M. Rice; Per Gunnar Wiklund; Kent D. Taylor; Alun Evans; Frank Kee; Jerome I. Rotter; Juha Karvanen; Kari Kuulasmaa; Gerardo Heiss; Peter Kraft; Lenore J. Launer; Albert Hofman; Marcello R P Markus; Lynda M. Rose; Kaisa Silander; Peter Wagner; Emelia J. Benjamin; Kurt Lohman; David J. Stott; Fernando Rivadeneira; Tamara B. Harris; Daniel Levy; Yongmei Liu; Eric B. Rimm; J. Wouter Jukema; Henry Volzke; Paul M. Ridker; Stefan Blankenberg; Oscar H. Franco; Vilmundur Gudnason; Bruce M. Psaty; Eric Boerwinkle; Christopher J. O'Donnell

doi:10.1371/journal.pone.0144997

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Abbas Dehghan, Joshua C. Bis, Charles C. White, Albert Vernon Smith, Alanna C. Morrison, L. Adrienne Cupples, Stella Trompet, Daniel I. Chasman, Thomas Lumley, Uwe Volker, Brendan M. Buckley, Jingzhong Ding, Majken K. Jensen, Aaron R. Folsom, Stephen B. Kritchevsky, Cynthia J. Girman, Ian Ford, Marcus Dorr, Veikko Salomaa, Andre G. UitterlindenGudny Eiriksdottir, Ramachandran S. Vasan, Nora Franceschini, Cara L. Carty, Jarmo Virtamo, Serkalem Demissie, Philippe Amouyel, Dominique Arveiler, Susan R. Heckbert, Jean Ferrieres, Pierre Ducimetiere, Nicholas L. Smith, Ying A. Wang, David S. Siscovick, Kenneth M. Rice, Per Gunnar Wiklund, Kent D. Taylor, Alun Evans, Frank Kee, Jerome I. Rotter, Juha Karvanen, Kari Kuulasmaa, Gerardo Heiss, Peter Kraft, Lenore J. Launer, Albert Hofman, Marcello R P Markus, Lynda M. Rose, Kaisa Silander, Peter Wagner, Emelia J. Benjamin, Kurt Lohman, David J. Stott, Fernando Rivadeneira, Tamara B. Harris, Daniel Levy, Yongmei Liu, Eric B. Rimm, J. Wouter Jukema, Henry Volzke, Paul M. Ridker, Stefan Blankenberg, Oscar H. Franco, Vilmundur Gudnason, Bruce M. Psaty, Eric Boerwinkle, Christopher J. O'Donnell

Epidemiology

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66 Scopus citations

Abstract

Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10^-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10^-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10^-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10^-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10^-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

Original language	English (US)
Article number	e0144997
Journal	PloS one
Volume	11
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0144997
State	Published - Mar 1 2016

Bibliographical note

Funding Information:
Merck Research Laboratories supported the genotyping of the Nurses’ Health and Health Professionals Follow-Up Studies though an unrestricted grant. Cynthia J. Girman is employed by and owns shares in Merck & Co. Inc. Ying A. Wang is currently an employee of Novartis. David J. Stott has received research funding from Bristol Myers Squibb for the PROSPER study (included in this report). Daniel Chasman has received funds from Amgen for genotyping and collaborative scientific support in the WGHS cohort. O. H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. David J. Stott has received research support from Merck Serono, Kabi-Fresenius, Pfizer, Astra-Zeneca, and consultancy/speaker fees for Boehringer Ingleheim, Nestle, Nutricia. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

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Dehghan, A., Bis, J. C., White, C. C., Smith, A. V., Morrison, A. C., Cupples, L. A., Trompet, S., Chasman, D. I., Lumley, T., Volker, U., Buckley, B. M., Ding, J., Jensen, M. K., Folsom, A. R., Kritchevsky, S. B., Girman, C. J., Ford, I., Dorr, M., Salomaa, V., ... O'Donnell, C. J. (2016). Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. PloS one, 11(3), Article e0144997. https://doi.org/10.1371/journal.pone.0144997

Dehghan, A, Bis, JC, White, CC, Smith, AV, Morrison, AC, Cupples, LA, Trompet, S, Chasman, DI, Lumley, T, Volker, U, Buckley, BM, Ding, J, Jensen, MK, Folsom, AR, Kritchevsky, SB, Girman, CJ, Ford, I, Dorr, M, Salomaa, V, Uitterlinden, AG, Eiriksdottir, G, Vasan, RS, Franceschini, N, Carty, CL, Virtamo, J, Demissie, S, Amouyel, P, Arveiler, D, Heckbert, SR, Ferrieres, J, Ducimetiere, P, Smith, NL, Wang, YA, Siscovick, DS, Rice, KM, Wiklund, PG, Taylor, KD, Evans, A, Kee, F, Rotter, JI, Karvanen, J, Kuulasmaa, K, Heiss, G, Kraft, P, Launer, LJ, Hofman, A, Markus, MRP, Rose, LM, Silander, K, Wagner, P, Benjamin, EJ, Lohman, K, Stott, DJ, Rivadeneira, F, Harris, TB, Levy, D, Liu, Y, Rimm, EB, Jukema, JW, Volzke, H, Ridker, PM, Blankenberg, S, Franco, OH, Gudnason, V, Psaty, BM, Boerwinkle, E & O'Donnell, CJ 2016, 'Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium', PloS one, vol. 11, no. 3, e0144997. https://doi.org/10.1371/journal.pone.0144997

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title = "Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium",

abstract = "Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.",

author = "Abbas Dehghan and Bis, {Joshua C.} and White, {Charles C.} and Smith, {Albert Vernon} and Morrison, {Alanna C.} and Cupples, {L. Adrienne} and Stella Trompet and Chasman, {Daniel I.} and Thomas Lumley and Uwe Volker and Buckley, {Brendan M.} and Jingzhong Ding and Jensen, {Majken K.} and Folsom, {Aaron R.} and Kritchevsky, {Stephen B.} and Girman, {Cynthia J.} and Ian Ford and Marcus Dorr and Veikko Salomaa and Uitterlinden, {Andre G.} and Gudny Eiriksdottir and Vasan, {Ramachandran S.} and Nora Franceschini and Carty, {Cara L.} and Jarmo Virtamo and Serkalem Demissie and Philippe Amouyel and Dominique Arveiler and Heckbert, {Susan R.} and Jean Ferrieres and Pierre Ducimetiere and Smith, {Nicholas L.} and Wang, {Ying A.} and Siscovick, {David S.} and Rice, {Kenneth M.} and Wiklund, {Per Gunnar} and Taylor, {Kent D.} and Alun Evans and Frank Kee and Rotter, {Jerome I.} and Juha Karvanen and Kari Kuulasmaa and Gerardo Heiss and Peter Kraft and Launer, {Lenore J.} and Albert Hofman and Markus, {Marcello R P} and Rose, {Lynda M.} and Kaisa Silander and Peter Wagner and Benjamin, {Emelia J.} and Kurt Lohman and Stott, {David J.} and Fernando Rivadeneira and Harris, {Tamara B.} and Daniel Levy and Yongmei Liu and Rimm, {Eric B.} and Jukema, {J. Wouter} and Henry Volzke and Ridker, {Paul M.} and Stefan Blankenberg and Franco, {Oscar H.} and Vilmundur Gudnason and Psaty, {Bruce M.} and Eric Boerwinkle and O'Donnell, {Christopher J.}",

note = "Funding Information: Merck Research Laboratories supported the genotyping of the Nurses{\textquoteright} Health and Health Professionals Follow-Up Studies though an unrestricted grant. Cynthia J. Girman is employed by and owns shares in Merck & Co. Inc. Ying A. Wang is currently an employee of Novartis. David J. Stott has received research funding from Bristol Myers Squibb for the PROSPER study (included in this report). Daniel Chasman has received funds from Amgen for genotyping and collaborative scientific support in the WGHS cohort. O. H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestl{\'e} Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. David J. Stott has received research support from Merck Serono, Kabi-Fresenius, Pfizer, Astra-Zeneca, and consultancy/speaker fees for Boehringer Ingleheim, Nestle, Nutricia. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. ",

year = "2016",

month = mar,

day = "1",

doi = "10.1371/journal.pone.0144997",

language = "English (US)",

volume = "11",

journal = "PloS one",

issn = "1932-6203",

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TY - JOUR

T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies

T2 - The CHARGE Consortium

AU - Dehghan, Abbas

AU - Bis, Joshua C.

AU - White, Charles C.

AU - Smith, Albert Vernon

AU - Morrison, Alanna C.

AU - Cupples, L. Adrienne

AU - Trompet, Stella

AU - Chasman, Daniel I.

AU - Lumley, Thomas

AU - Volker, Uwe

AU - Buckley, Brendan M.

AU - Ding, Jingzhong

AU - Jensen, Majken K.

AU - Folsom, Aaron R.

AU - Kritchevsky, Stephen B.

AU - Girman, Cynthia J.

AU - Ford, Ian

AU - Dorr, Marcus

AU - Salomaa, Veikko

AU - Uitterlinden, Andre G.

AU - Eiriksdottir, Gudny

AU - Vasan, Ramachandran S.

AU - Franceschini, Nora

AU - Carty, Cara L.

AU - Virtamo, Jarmo

AU - Demissie, Serkalem

AU - Amouyel, Philippe

AU - Arveiler, Dominique

AU - Heckbert, Susan R.

AU - Ferrieres, Jean

AU - Ducimetiere, Pierre

AU - Smith, Nicholas L.

AU - Wang, Ying A.

AU - Siscovick, David S.

AU - Rice, Kenneth M.

AU - Wiklund, Per Gunnar

AU - Taylor, Kent D.

AU - Evans, Alun

AU - Kee, Frank

AU - Rotter, Jerome I.

AU - Karvanen, Juha

AU - Kuulasmaa, Kari

AU - Heiss, Gerardo

AU - Kraft, Peter

AU - Launer, Lenore J.

AU - Hofman, Albert

AU - Markus, Marcello R P

AU - Rose, Lynda M.

AU - Silander, Kaisa

AU - Wagner, Peter

AU - Benjamin, Emelia J.

AU - Lohman, Kurt

AU - Stott, David J.

AU - Rivadeneira, Fernando

AU - Harris, Tamara B.

AU - Levy, Daniel

AU - Liu, Yongmei

AU - Rimm, Eric B.

AU - Jukema, J. Wouter

AU - Volzke, Henry

AU - Ridker, Paul M.

AU - Blankenberg, Stefan

AU - Franco, Oscar H.

AU - Gudnason, Vilmundur

AU - Psaty, Bruce M.

AU - Boerwinkle, Eric

AU - O'Donnell, Christopher J.

N1 - Funding Information: Merck Research Laboratories supported the genotyping of the Nurses’ Health and Health Professionals Follow-Up Studies though an unrestricted grant. Cynthia J. Girman is employed by and owns shares in Merck & Co. Inc. Ying A. Wang is currently an employee of Novartis. David J. Stott has received research funding from Bristol Myers Squibb for the PROSPER study (included in this report). Daniel Chasman has received funds from Amgen for genotyping and collaborative scientific support in the WGHS cohort. O. H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article. Psaty serves on the DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. David J. Stott has received research support from Merck Serono, Kabi-Fresenius, Pfizer, Astra-Zeneca, and consultancy/speaker fees for Boehringer Ingleheim, Nestle, Nutricia. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

AB - Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stageGWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with totalmortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

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Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

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