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 Völker; Brendan M Buckley; Jingzhong Ding; Majken K Jensen; Aaron R Folsom; Stephen B Kritchevsky; Cynthia J Girman; Ian Ford; Marcus Dörr; Veikko Salomaa; André G Uitterlinden; Gudny Eiriksdottir; Ramachandran S Vasan; Nora Franceschini; Cara L Carty; Jarmo Virtamo; Serkalem Demissie; Philippe Amouyel; Dominique Arveiler; Susan R Heckbert; Jean Ferrières; Pierre Ducimetière; 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 Völzke; 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 Völker, Brendan M Buckley, Jingzhong Ding, Majken K Jensen, Aaron R Folsom, Stephen B Kritchevsky, Cynthia J Girman, Ian Ford, Marcus Dörr, Veikko Salomaa, André G UitterlindenGudny Eiriksdottir, Ramachandran S Vasan, Nora Franceschini, Cara L Carty, Jarmo Virtamo, Serkalem Demissie, Philippe Amouyel, Dominique Arveiler, Susan R Heckbert, Jean Ferrières, Pierre Ducimetière, 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 Völzke, Paul M Ridker, Stefan Blankenberg, Oscar H Franco, Vilmundur Gudnason, Bruce M Psaty, Eric Boerwinkle, Christopher J O'Donnell

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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-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI 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 total mortality 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
Pages (from-to)	e0144997
Journal	PloS one
Volume	11
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0144997
Publication status	Published - 07 Mar 2016

Keywords

Aged
Cohort Studies
Cooperative Behavior
Coronary Artery Disease
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Middle Aged
Myocardial Infarction
Polymorphism, Single Nucleotide
Prospective Studies
Journal Article
Research Support, Non-U.S. Gov't

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Genome-wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies
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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., Völker, U., Buckley, B. M., Ding, J., Jensen, M. K., Folsom, A. R., Kritchevsky, S. B., Girman, C. J., Ford, I., Dörr, 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), e0144997. https://doi.org/10.1371/journal.pone.0144997

@article{572adbe8ad7d434685317ed3d6d5e02c,

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-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI 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 total mortality 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.",

keywords = "Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, Journal Article, Research Support, Non-U.S. Gov't",

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 V{\"o}lker 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 D{\"o}rr and Veikko Salomaa and Uitterlinden, {Andr{\'e} 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 Ferri{\`e}res and Pierre Ducimeti{\`e}re and Smith, {Nicholas L} and Wang, {Ying A} and Siscovick, {David S} and Rice, {Kenneth M} and Per-Gunnar Wiklund 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 V{\"o}lzke 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}",

year = "2016",

month = mar,

day = "7",

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

language = "English",

volume = "11",

pages = "e0144997",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

}

Dehghan, A, Bis, JC, White, CC, Smith, AV, Morrison, AC, Cupples, LA, Trompet, S, Chasman, DI, Lumley, T, Völker, U, Buckley, BM, Ding, J, Jensen, MK, Folsom, AR, Kritchevsky, SB, Girman, CJ, Ford, I, Dörr, M, Salomaa, V, Uitterlinden, AG, Eiriksdottir, G, Vasan, RS, Franceschini, N, Carty, CL, Virtamo, J, Demissie, S, Amouyel, P, Arveiler, D, Heckbert, SR, Ferrières, J, Ducimetière, P, Smith, NL, Wang, YA, Siscovick, DS, Rice, KM, Wiklund, P-G, 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, Völzke, 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, pp. e0144997. https://doi.org/10.1371/journal.pone.0144997

TY - JOUR

T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: 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 - Völker, 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 - Dörr, Marcus

AU - Salomaa, Veikko

AU - Uitterlinden, André 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 - Ferrières, Jean

AU - Ducimetière, 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 - Völzke, 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

PY - 2016/3/7

Y1 - 2016/3/7

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-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI 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 total mortality 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-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI 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 total mortality 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.

KW - Aged

KW - Cohort Studies

KW - Cooperative Behavior

KW - Coronary Artery Disease

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0144997

DO - 10.1371/journal.pone.0144997

M3 - Article

C2 - 26950853

SN - 1932-6203

VL - 11

SP - e0144997

JO - PloS one

JF - PloS one

IS - 3

ER -

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

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