A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Majid Nikpay; Anuj Goel; Hong-Hee Won; Leanne M. Hall; Christina Willenborg; Stavroula Kanoni; Danish Saleheen; Theodosios  Kyriakou; Christopher P. Nelson; Jemma C. Hopewell; Thomas R. Webb; Lingyao Zeng; Abbas Dehghan; Maris Elver; Sebastian M. Armasu; Kirsi Auro; Andrew Bjonnes; Daniel I. Chasman; Shufeng Chen; Ian Ford; Nora Franceschini; Christian Gieger; Christopher Grace; Stefan Gustafsson; Jie Huang; Shih-Jen Hwang; Yun Kyoung Kim; Marcus E. Kleber; King Wai Lau; Xiangfeng Lu; Yingchang Lu; Leo-Pekka Lyytikäinen; Evelin Mihailov; Alanna C. Morrison; Natalia Pervjakova; Liming Qu; Lynda M. Rose; Elias Salfati; Richa Saxena; Markus Scholz; Albert V. Smith; Emmi Tikkanen; Andre Uitterlinden; Xueli Yang; Weihua Zhang; Wei Zhao; Mariza de Andrade; Paul S. de Vries; Natalie R. van Zuydam; Colin N. Palmer; for the CARDIoGRAMplusC4D Consortium; Hugh Watkins; Sekar Kathiresan; Ruth McPherson; Martin Farrall

doi:10.1038/ng.3396

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M. Hall, Christina Willenborg, Stavroula Kanoni, Danish Saleheen, Theodosios Kyriakou, Christopher P. Nelson, Jemma C. Hopewell, Thomas R. Webb, Lingyao Zeng, Abbas Dehghan, Maris Elver, Sebastian M. Armasu, Kirsi Auro, Andrew Bjonnes, Daniel I. Chasman, Shufeng Chen, Ian FordNora Franceschini, Christian Gieger, Christopher Grace, Stefan Gustafsson, Jie Huang, Shih-Jen Hwang, Yun Kyoung Kim, Marcus E. Kleber, King Wai Lau, Xiangfeng Lu, Yingchang Lu, Leo-Pekka Lyytikäinen, Evelin Mihailov, Alanna C. Morrison, Natalia Pervjakova, Liming Qu, Lynda M. Rose, Elias Salfati, Richa Saxena, Markus Scholz, Albert V. Smith, Emmi Tikkanen, Andre Uitterlinden, Xueli Yang, Weihua Zhang, Wei Zhao, Mariza de Andrade, Paul S. de Vries, Natalie R. van Zuydam, Colin N. Palmer, for the CARDIoGRAMplusC4D Consortium, Hugh Watkins (Lead / Corresponding author), Sekar Kathiresan (Lead / Corresponding author), Ruth McPherson (Lead / Corresponding author), Martin Farrall (Lead / Corresponding author)

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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 casual 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
Early online date	7 Sept 2015
DOIs	https://doi.org/10.1038/ng.3396
Publication status	Published - Oct 2015

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CAD1000G2015Final published version, 4.39 MB

Palmer, Colin
- Population Health and Genomics - Professor (Teaching and Research) of Pharmacogenomics
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Nikpay, M., Goel, A., Won, H.-H., Hall, L. M., Willenborg, C., Kanoni, S., Saleheen, D., Kyriakou, T., Nelson, C. P., Hopewell, J. C., Webb, T. R., Zeng, L., Dehghan, A., Elver, M., Armasu, S. M., Auro, K., Bjonnes, A., Chasman, D. I., Chen, S., ... Farrall, M. (2015). A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nature Genetics, 47(10), 1121-1130. https://doi.org/10.1038/ng.3396

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title = "A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease",

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 casual 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.",

author = "Majid Nikpay and Anuj Goel and Hong-Hee Won and Hall, {Leanne M.} and Christina Willenborg and Stavroula Kanoni and Danish Saleheen and Theodosios Kyriakou and Nelson, {Christopher P.} and Hopewell, {Jemma C.} and Webb, {Thomas R.} and Lingyao Zeng and Abbas Dehghan and Maris Elver and Armasu, {Sebastian M.} and Kirsi Auro and Andrew Bjonnes and Chasman, {Daniel I.} and Shufeng Chen and Ian Ford and Nora Franceschini and Christian Gieger and Christopher Grace and Stefan Gustafsson and Jie Huang and Shih-Jen Hwang and Kim, {Yun Kyoung} and Kleber, {Marcus E.} and Lau, {King Wai} and Xiangfeng Lu and Yingchang Lu and Leo-Pekka Lyytik{\"a}inen and Evelin Mihailov and Morrison, {Alanna C.} and Natalia Pervjakova and Liming Qu and Rose, {Lynda M.} and Elias Salfati and Richa Saxena and Markus Scholz and Smith, {Albert V.} and Emmi Tikkanen and Andre Uitterlinden and Xueli Yang and Weihua Zhang and Wei Zhao and {de Andrade}, Mariza and {de Vries}, {Paul S.} and {van Zuydam}, {Natalie R.} and Palmer, {Colin N.} and {for the CARDIoGRAMplusC4D Consortium} and Hugh Watkins and Sekar Kathiresan and Ruth McPherson and Martin Farrall",

year = "2015",

month = oct,

doi = "10.1038/ng.3396",

language = "English",

volume = "47",

pages = "1121--1130",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

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Nikpay, M, Goel, A, Won, H-H, Hall, LM, Willenborg, C, Kanoni, S, Saleheen, D, Kyriakou, T, Nelson, CP, Hopewell, JC, Webb, TR, Zeng, L, Dehghan, A, Elver, M, Armasu, SM, Auro, K, Bjonnes, A, Chasman, DI, Chen, S, Ford, I, Franceschini, N, Gieger, C, Grace, C, Gustafsson, S, Huang, J, Hwang, S-J, Kim, YK, Kleber, ME, Lau, KW, Lu, X, Lu, Y, Lyytikäinen, L-P, Mihailov, E, Morrison, AC, Pervjakova, N, Qu, L, Rose, LM, Salfati, E, Saxena, R, Scholz, M, Smith, AV, Tikkanen, E, Uitterlinden, A, Yang, X, Zhang, W, Zhao, W, de Andrade, M, de Vries, PS, van Zuydam, NR, Palmer, CN, for the CARDIoGRAMplusC4D Consortium, Watkins, H, Kathiresan, S, McPherson, R & Farrall, M 2015, 'A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease', Nature Genetics, vol. 47, no. 10, pp. 1121-1130. https://doi.org/10.1038/ng.3396

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 - Hopewell, Jemma C.

AU - Webb, Thomas R.

AU - Zeng, Lingyao

AU - Dehghan, Abbas

AU - Elver, Maris

AU - Armasu, Sebastian M.

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 - Palmer, Colin N.

AU - for the CARDIoGRAMplusC4D Consortium

AU - Watkins, Hugh

AU - Kathiresan, Sekar

AU - McPherson, Ruth

AU - Farrall, Martin

PY - 2015/10

Y1 - 2015/10

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 casual 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 casual 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.

U2 - 10.1038/ng.3396

DO - 10.1038/ng.3396

M3 - Article

C2 - 26343387

SN - 1061-4036

VL - 47

SP - 1121

EP - 1130

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

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