Association analyses based on false discovery rate implicate new loci for coronary artery disease

Christopher P. Nelson; Anuj Goel; Adam S. Butterworth; Stavroula Kanoni; Tom R. Webb; Eirini Marouli; Lingyao Zeng; Ioanna Ntalla; Florence Y. Lai; Jemma C. Hopewell; Olga Giannakopoulou; Tao Jiang; Stephen E. Hamby; Emanuele di Angelantonio; Themistocles L. Assimes; Erwin P. Bottinger; John C. Chambers; Robert Clarke; Colin N. A. Palmer; Richard M. Cubbon; Patrick Ellinor; Raili Ermel; Evangelos Evangelou; Paul W. Franks; Christopher Grace; Dongfeng Gu; Aroon D. Hingorani; Joanna M. M. Howson; Erik Ingelsson; Adnan Kastrati; Thorsten Kessler; Theodosios Kyriakou; Terho Lehtimäki; Xiangfeng Lu; Yingchang Lu; Winfried März; Ruth McPherson; Andres Metspalu; Mar Pujades-Rodriguez; Arno Ruusalepp; Eric E. Schadt; Amand F. Schmidt; Michael J. Sweeting; Pierre A. Zalloua; Kamal Alghalayini; Bernard D. Keavney; Jaspal S. Kooner; Ruth J. F. Loos; Riyaz S. Patel; Martin K. Rutter; Maciej Tomaszewski; Ioanna Tzoulaki; Eleftheria Zeggini; Jeanette Erdmann; George Dedoussis; Johan L. M. Björkegren; Heribert Schunkert; Martin Farrall; John Danesh; Nilesh J. Samani; Hugh Watkins; Panos Deloukas

doi:https://doi.org/10.1038/ng.3913

Association analyses based on false discovery rate implicate new loci for coronary artery disease

Christopher P. Nelson, Anuj Goel, Adam S. Butterworth, Stavroula Kanoni, Tom R. Webb, Eirini Marouli, Lingyao Zeng, Ioanna Ntalla, Florence Y. Lai, Jemma C. Hopewell, Olga Giannakopoulou, Tao Jiang, Stephen E. Hamby, Emanuele di Angelantonio, Themistocles L. Assimes, Erwin P. Bottinger, John C. Chambers, Robert Clarke, Colin N. A. Palmer, Richard M. CubbonPatrick Ellinor, Raili Ermel, Evangelos Evangelou, Paul W. Franks, Christopher Grace, Dongfeng Gu, Aroon D. Hingorani, Joanna M. M. Howson, Erik Ingelsson, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Terho Lehtimäki, Xiangfeng Lu, Yingchang Lu, Winfried März, Ruth McPherson, Andres Metspalu, Mar Pujades-Rodriguez, Arno Ruusalepp, Eric E. Schadt, Amand F. Schmidt, Michael J. Sweeting, Pierre A. Zalloua, Kamal Alghalayini, Bernard D. Keavney, Jaspal S. Kooner, Ruth J. F. Loos, Riyaz S. Patel, Martin K. Rutter, Maciej Tomaszewski, Ioanna Tzoulaki, Eleftheria Zeggini, Jeanette Erdmann, George Dedoussis, Johan L. M. Björkegren, Heribert Schunkert, Martin Farrall, John Danesh, Nilesh J. Samani, Hugh Watkins, Panos Deloukas

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

Original language	English
Pages (from-to)	1385-1391
Journal	Nature Genetics
Volume	49
Issue number	9
DOIs	https://doi.org/10.1038/ng.3913
Publication status	Published - 1 Sept 2017
Externally published	Yes

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Nelson, C. P., Goel, A., Butterworth, A. S., Kanoni, S., Webb, T. R., Marouli, E., Zeng, L., Ntalla, I., Lai, F. Y., Hopewell, J. C., Giannakopoulou, O., Jiang, T., Hamby, S. E., di Angelantonio, E., Assimes, T. L., Bottinger, E. P., Chambers, J. C., Clarke, R., Palmer, C. N. A., ... Deloukas, P. (2017). Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nature Genetics, 49(9), 1385-1391. https://doi.org/10.1038/ng.3913

@article{775f7294b453428bbf7b3ab651289be8,

title = "Association analyses based on false discovery rate implicate new loci for coronary artery disease",

abstract = "Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.",

author = "Nelson, {Christopher P.} and Anuj Goel and Butterworth, {Adam S.} and Stavroula Kanoni and Webb, {Tom R.} and Eirini Marouli and Lingyao Zeng and Ioanna Ntalla and Lai, {Florence Y.} and Hopewell, {Jemma C.} and Olga Giannakopoulou and Tao Jiang and Hamby, {Stephen E.} and {di Angelantonio}, Emanuele and Assimes, {Themistocles L.} and Bottinger, {Erwin P.} and Chambers, {John C.} and Robert Clarke and Palmer, {Colin N. A.} and Cubbon, {Richard M.} and Patrick Ellinor and Raili Ermel and Evangelos Evangelou and Franks, {Paul W.} and Christopher Grace and Dongfeng Gu and Hingorani, {Aroon D.} and Howson, {Joanna M. M.} and Erik Ingelsson and Adnan Kastrati and Thorsten Kessler and Theodosios Kyriakou and Terho Lehtim{\"a}ki and Xiangfeng Lu and Yingchang Lu and Winfried M{\"a}rz and Ruth McPherson and Andres Metspalu and Mar Pujades-Rodriguez and Arno Ruusalepp and Schadt, {Eric E.} and Schmidt, {Amand F.} and Sweeting, {Michael J.} and Zalloua, {Pierre A.} and Kamal Alghalayini and Keavney, {Bernard D.} and Kooner, {Jaspal S.} and Loos, {Ruth J. F.} and Patel, {Riyaz S.} and Rutter, {Martin K.} and Maciej Tomaszewski and Ioanna Tzoulaki and Eleftheria Zeggini and Jeanette Erdmann and George Dedoussis and Bj{\"o}rkegren, {Johan L. M.} and Heribert Schunkert and Martin Farrall and John Danesh and Samani, {Nilesh J.} and Hugh Watkins and Panos Deloukas",

year = "2017",

month = sep,

day = "1",

doi = "https://doi.org/10.1038/ng.3913",

language = "English",

volume = "49",

pages = "1385--1391",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "9",

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Nelson, CP, Goel, A, Butterworth, AS, Kanoni, S, Webb, TR, Marouli, E, Zeng, L, Ntalla, I, Lai, FY, Hopewell, JC, Giannakopoulou, O, Jiang, T, Hamby, SE, di Angelantonio, E, Assimes, TL, Bottinger, EP, Chambers, JC, Clarke, R, Palmer, CNA, Cubbon, RM, Ellinor, P, Ermel, R, Evangelou, E, Franks, PW, Grace, C, Gu, D, Hingorani, AD, Howson, JMM, Ingelsson, E, Kastrati, A, Kessler, T, Kyriakou, T, Lehtimäki, T, Lu, X, Lu, Y, März, W, McPherson, R, Metspalu, A, Pujades-Rodriguez, M, Ruusalepp, A, Schadt, EE, Schmidt, AF, Sweeting, MJ, Zalloua, PA, Alghalayini, K, Keavney, BD, Kooner, JS, Loos, RJF, Patel, RS, Rutter, MK, Tomaszewski, M, Tzoulaki, I, Zeggini, E, Erdmann, J, Dedoussis, G, Björkegren, JLM, Schunkert, H, Farrall, M, Danesh, J, Samani, NJ, Watkins, H & Deloukas, P 2017, 'Association analyses based on false discovery rate implicate new loci for coronary artery disease', Nature Genetics, vol. 49, no. 9, pp. 1385-1391. https://doi.org/10.1038/ng.3913

TY - JOUR

T1 - Association analyses based on false discovery rate implicate new loci for coronary artery disease

AU - Nelson, Christopher P.

AU - Goel, Anuj

AU - Butterworth, Adam S.

AU - Kanoni, Stavroula

AU - Webb, Tom R.

AU - Marouli, Eirini

AU - Zeng, Lingyao

AU - Ntalla, Ioanna

AU - Lai, Florence Y.

AU - Hopewell, Jemma C.

AU - Giannakopoulou, Olga

AU - Jiang, Tao

AU - Hamby, Stephen E.

AU - di Angelantonio, Emanuele

AU - Assimes, Themistocles L.

AU - Bottinger, Erwin P.

AU - Chambers, John C.

AU - Clarke, Robert

AU - Palmer, Colin N. A.

AU - Cubbon, Richard M.

AU - Ellinor, Patrick

AU - Ermel, Raili

AU - Evangelou, Evangelos

AU - Franks, Paul W.

AU - Grace, Christopher

AU - Gu, Dongfeng

AU - Hingorani, Aroon D.

AU - Howson, Joanna M. M.

AU - Ingelsson, Erik

AU - Kastrati, Adnan

AU - Kessler, Thorsten

AU - Kyriakou, Theodosios

AU - Lehtimäki, Terho

AU - Lu, Xiangfeng

AU - Lu, Yingchang

AU - März, Winfried

AU - McPherson, Ruth

AU - Metspalu, Andres

AU - Pujades-Rodriguez, Mar

AU - Ruusalepp, Arno

AU - Schadt, Eric E.

AU - Schmidt, Amand F.

AU - Sweeting, Michael J.

AU - Zalloua, Pierre A.

AU - Alghalayini, Kamal

AU - Keavney, Bernard D.

AU - Kooner, Jaspal S.

AU - Loos, Ruth J. F.

AU - Patel, Riyaz S.

AU - Rutter, Martin K.

AU - Tomaszewski, Maciej

AU - Tzoulaki, Ioanna

AU - Zeggini, Eleftheria

AU - Erdmann, Jeanette

AU - Dedoussis, George

AU - Björkegren, Johan L. M.

AU - Schunkert, Heribert

AU - Farrall, Martin

AU - Danesh, John

AU - Samani, Nilesh J.

AU - Watkins, Hugh

AU - Deloukas, Panos

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

AB - Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

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DO - https://doi.org/10.1038/ng.3913

M3 - Article

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SN - 1061-4036

VL - 49

SP - 1385

EP - 1391

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Association analyses based on false discovery rate implicate new loci for coronary artery disease

Abstract

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