Abstract
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 <MAF <0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
| Original language | English |
|---|---|
| Pages (from-to) | 1121-1130 |
| Number of pages | 10 |
| Journal | Nature Genetics |
| Volume | 47 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Sep 29 2015 |
ASJC Scopus subject areas
- Genetics
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. / Nikpay, Majid; Goel, Anuj; Won, Hong Hee; Hall, Leanne M.; Willenborg, Christina; Kanoni, Stavroula; Saleheen, Danish; Kyriakou, Theodosios; Nelson, Christopher P.; CHopewell, Jemma; Webb, Thomas R.; Zeng, Lingyao; Dehghan, Abbas; Alver, Maris; MArmasu, Sebastian; Auro, Kirsi; Bjonnes, Andrew; Chasman, Daniel I.; Chen, Shufeng; Ford, Ian; Franceschini, Nora; Gieger, Christian; Grace, Christopher; Gustafsson, Stefan; Huang, Jie; Hwang, Shih Jen; Kim, Yun Kyoung; Kleber, Marcus E.; Lau, King Wai; Lu, Xiangfeng; Lu, Yingchang; Lyytikäinen, Leo Pekka; Mihailov, Evelin; Morrison, Alanna C.; Pervjakova, Natalia; Qu, Liming; Rose, Lynda M.; Salfati, Elias; Saxena, Richa; Scholz, Markus; Smith, Albert V.; Tikkanen, Emmi; Uitterlinden, Andre; Yang, Xueli; Zhang, Weihua; Zhao, Wei; De Andrade, Mariza; De Vries, Paul S.; Van Zuydam, Natalie R.; Anand, Sonia S.; Bertram, Lars; Beutner, Frank; Dedoussis, George; Frossard, Philippe; Gauguier, Dominique; Goodall, Alison H.; Gottesman, Omri; Haber, Marc; Han, Bok Ghee; Huang, Jianfeng; Jalilzadeh, Shapour; Kessler, Thorsten; König, Inke R.; Lannfelt, Lars; Lieb, Wolfgang; Lind, Lars; MLindgren, Cecilia; Lokki, Marja Liisa; Magnusson, Patrik K.; Mallick, Nadeem H.; Mehra, Narinder; Meitinger, Thomas; Memon, Fazal Uur Rehman; Morris, Andrew P.; Nieminen, Markku S.; Pedersen, Nancy L.; Peters, Annette; Rallidis, Loukianos S.; Rasheed, Asif; Samuel, Maria; Shah, Svati H.; Sinisalo, Juha; EStirrups, Kathleen; Trompet, Stella; Wang, Laiyuan; Zaman, Khan S.; Ardissino, Diego; Boerwinkle, Eric; Borecki, Ingrid B.; Bottinger, Erwin P.; Buring, Julie E.; Chambers, John C.; Collins, Rory; Cupples, Ladrienne; Danesh, John; Demuth, Ilja; Elosua, Roberto; Epstein, Stephen E.; Esko, Tõnu; Feitosa, Mary F.; Franco, Oscar H.; Franzosi, Maria Grazia; Granger, Christopher B.; Gu, Dongfeng; Gudnason, Vilmundur; SHall, Alistair; Hamsten, Anders; Harris, Tamara B.; LHazen, Stanley; Hengstenberg, Christian; Hofman, Albert; Ingelsson, Erik; Iribarren, Carlos; Jukema, J. Wouter; Karhunen, Pekka J.; Kim, Bong Jo; Kooner, Jaspal S.; Kullo, Iftikhar J.; Lehtimäki, Terho; Loos, Ruth J F; Melander, Olle; Metspalu, Andres; März, Winfried; Palmer, Colin N.; Perola, Markus; Quertermous, Thomas; Rader, Daniel J.; Ridker, Paul M.; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Sanghera, Dharambir K.; Schwartz, Stephen M.; Seedorf, Udo; Stewart, Alexandre F.; Stott, David J.; Thiery, Joachim; Zalloua, Pierre A.; O'Donnell, Christopher J.; Reilly, Muredach P.; Assimes, Themistocles L.; Thompson, John R.; Erdmann, Jeanette; Clarke, Robert; Watkins, Hugh; Kathiresan, Sekar; McPherson, Ruth; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J.; Farrall, Martin.
In: Nature Genetics, Vol. 47, No. 10, 29.09.2015, p. 1121-1130.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
AU - Nikpay, Majid
AU - Goel, Anuj
AU - Won, Hong Hee
AU - Hall, Leanne M.
AU - Willenborg, Christina
AU - Kanoni, Stavroula
AU - Saleheen, Danish
AU - Kyriakou, Theodosios
AU - Nelson, Christopher P.
AU - CHopewell, Jemma
AU - Webb, Thomas R.
AU - Zeng, Lingyao
AU - Dehghan, Abbas
AU - Alver, Maris
AU - MArmasu, Sebastian
AU - Auro, Kirsi
AU - Bjonnes, Andrew
AU - Chasman, Daniel I.
AU - Chen, Shufeng
AU - Ford, Ian
AU - Franceschini, Nora
AU - Gieger, Christian
AU - Grace, Christopher
AU - Gustafsson, Stefan
AU - Huang, Jie
AU - Hwang, Shih Jen
AU - Kim, Yun Kyoung
AU - Kleber, Marcus E.
AU - Lau, King Wai
AU - Lu, Xiangfeng
AU - Lu, Yingchang
AU - Lyytikäinen, Leo Pekka
AU - Mihailov, Evelin
AU - Morrison, Alanna C.
AU - Pervjakova, Natalia
AU - Qu, Liming
AU - Rose, Lynda M.
AU - Salfati, Elias
AU - Saxena, Richa
AU - Scholz, Markus
AU - Smith, Albert V.
AU - Tikkanen, Emmi
AU - Uitterlinden, Andre
AU - Yang, Xueli
AU - Zhang, Weihua
AU - Zhao, Wei
AU - De Andrade, Mariza
AU - De Vries, Paul S.
AU - Van Zuydam, Natalie R.
AU - Anand, Sonia S.
AU - Bertram, Lars
AU - Beutner, Frank
AU - Dedoussis, George
AU - Frossard, Philippe
AU - Gauguier, Dominique
AU - Goodall, Alison H.
AU - Gottesman, Omri
AU - Haber, Marc
AU - Han, Bok Ghee
AU - Huang, Jianfeng
AU - Jalilzadeh, Shapour
AU - Kessler, Thorsten
AU - König, Inke R.
AU - Lannfelt, Lars
AU - Lieb, Wolfgang
AU - Lind, Lars
AU - MLindgren, Cecilia
AU - Lokki, Marja Liisa
AU - Magnusson, Patrik K.
AU - Mallick, Nadeem H.
AU - Mehra, Narinder
AU - Meitinger, Thomas
AU - Memon, Fazal Uur Rehman
AU - Morris, Andrew P.
AU - Nieminen, Markku S.
AU - Pedersen, Nancy L.
AU - Peters, Annette
AU - Rallidis, Loukianos S.
AU - Rasheed, Asif
AU - Samuel, Maria
AU - Shah, Svati H.
AU - Sinisalo, Juha
AU - EStirrups, Kathleen
AU - Trompet, Stella
AU - Wang, Laiyuan
AU - Zaman, Khan S.
AU - Ardissino, Diego
AU - Boerwinkle, Eric
AU - Borecki, Ingrid B.
AU - Bottinger, Erwin P.
AU - Buring, Julie E.
AU - Chambers, John C.
AU - Collins, Rory
AU - Cupples, Ladrienne
AU - Danesh, John
AU - Demuth, Ilja
AU - Elosua, Roberto
AU - Epstein, Stephen E.
AU - Esko, Tõnu
AU - Feitosa, Mary F.
AU - Franco, Oscar H.
AU - Franzosi, Maria Grazia
AU - Granger, Christopher B.
AU - Gu, Dongfeng
AU - Gudnason, Vilmundur
AU - SHall, Alistair
AU - Hamsten, Anders
AU - Harris, Tamara B.
AU - LHazen, Stanley
AU - Hengstenberg, Christian
AU - Hofman, Albert
AU - Ingelsson, Erik
AU - Iribarren, Carlos
AU - Jukema, J. Wouter
AU - Karhunen, Pekka J.
AU - Kim, Bong Jo
AU - Kooner, Jaspal S.
AU - Kullo, Iftikhar J.
AU - Lehtimäki, Terho
AU - Loos, Ruth J F
AU - Melander, Olle
AU - Metspalu, Andres
AU - März, Winfried
AU - Palmer, Colin N.
AU - Perola, Markus
AU - Quertermous, Thomas
AU - Rader, Daniel J.
AU - Ridker, Paul M.
AU - Ripatti, Samuli
AU - Roberts, Robert
AU - Salomaa, Veikko
AU - Sanghera, Dharambir K.
AU - Schwartz, Stephen M.
AU - Seedorf, Udo
AU - Stewart, Alexandre F.
AU - Stott, David J.
AU - Thiery, Joachim
AU - Zalloua, Pierre A.
AU - O'Donnell, Christopher J.
AU - Reilly, Muredach P.
AU - Assimes, Themistocles L.
AU - Thompson, John R.
AU - Erdmann, Jeanette
AU - Clarke, Robert
AU - Watkins, Hugh
AU - Kathiresan, Sekar
AU - McPherson, Ruth
AU - Deloukas, Panos
AU - Schunkert, Heribert
AU - Samani, Nilesh J.
AU - Farrall, Martin
PY - 2015/9/29
Y1 - 2015/9/29
N2 - Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 <MAF <0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
AB - Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 <MAF <0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
UR - http://www.scopus.com/inward/record.url?scp=84942987885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84942987885&partnerID=8YFLogxK
U2 - 10.1038/ng.3396
DO - 10.1038/ng.3396
M3 - Article
AN - SCOPUS:84942987885
VL - 47
SP - 1121
EP - 1130
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 10
ER -