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 & 31 others Patrick T. 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, EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group

Research output: Contribution to journalLetter

64 Citations (Scopus)

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; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 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 languageEnglish
Pages (from-to)1385-1391
Number of pages6
JournalNature Genetics
Volume49
Issue number9
Early online date17 Jul 2017
DOIs
Publication statusPublished - Sep 2017

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Coronary Artery Disease
Genome-Wide Association Study
Genome
Phenotype
Morphogenesis
Lipid Metabolism
Blood Vessels
Meta-Analysis
Nitric Oxide
Inflammation

Keywords

  • Journal article
  • Cardiovascular diseases
  • Genetics
  • Genome-wide association studies
  • Genome-wide association studies

Cite this

Nelson, C. P., Goel, A., Butterworth, A. S., Kanoni, S., Webb, T. R., Marouli, E., ... EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group (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
Nelson, Christopher P. ; Goel, Anuj ; Butterworth, Adam S. ; Kanoni, Stavroula ; Webb, Tom R ; Marouli, Eirini ; Zeng, Lingyao ; Ntalla, Ioanna ; Lai, Florence Y ; Hopewell, Jemma C. ; Giannakopoulou, Olga ; Jiang, Tao ; Hamby, Stephen E. ; Di Angelantonio, Emanuele ; Assimes, Themistocles L. ; Bottinger, Erwin P. ; Chambers, John C. ; Clarke, Robert ; Palmer, Colin N A ; Cubbon, Richard M. ; Ellinor, Patrick T. ; Ermel, Raili ; Evangelou, Evangelos ; Franks, Paul W. ; Grace, Christopher ; Gu, Dongfeng ; Hingorani, Aroon D. ; Howson, Joanna M. M. ; Ingelsson, Erik ; Kastrati, Adnan ; Kessler, Thorsten ; Kyriakou, Theodosios ; Lehtimäki, Terho ; Lu, Xiangfeng ; Lu, Yingchang ; März, Winfried ; McPherson, Ruth ; Metspalu, Andres ; Pujades-Rodriguez, Mar ; Ruusalepp, Arno ; Schadt, Eric E. ; Schmidt, Amand F ; Sweeting, Michael J ; Zalloua, Pierre A. ; AlGhalayini, Kamal ; Keavney, Bernard D. ; Kooner, Jaspal S. ; Loos, Ruth J. F. ; Patel, Riyaz S ; Rutter, Martin K ; EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group . / Association analyses based on false discovery rate implicate new loci for coronary artery disease. In: Nature Genetics. 2017 ; Vol. 49, No. 9. pp. 1385-1391.
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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; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 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.",
keywords = "Journal article, Cardiovascular diseases , Genetics , Genome-wide association studies , Genome-wide association studies",
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 Ellinor, {Patrick T.} 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 {EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group}",
note = "P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. E.I. is an advisor and consultant for Precision Wellness, Inc., and an advisor for Cellink for work unrelated to the present project. M.K.R. has acted as a consultant for GSK, Roche, Ascensia and MSD and participated in advisory board meetings on their behalf. M.K.R. has received lecture fees from MSD and grant support from Novo Nordisk, MSD and GSK. J.L.M.B. is the founder and chairman of Clinical Gene Networks. CGN has financially contributed to the STARNET study. J.L.M.B., E.E.S. and A.R. are on the board of directors for CGN. J.L.M.B. and A.R. own equity in CGN and receive financial compensation from CGN.",
year = "2017",
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language = "English",
volume = "49",
pages = "1385--1391",
journal = "Nature Genetics",
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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, PT, 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 & EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group 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

Association analyses based on false discovery rate implicate new loci for coronary artery disease. / Nelson, Christopher P.; Goel, Anuj; Butterworth, Adam S.; Kanoni, Stavroula; Webb, Tom R; Marouli, Eirini; Zeng, Lingyao; Ntalla, Ioanna; Lai, Florence Y; Hopewell, Jemma C.; Giannakopoulou, Olga; Jiang, Tao; Hamby, Stephen E.; Di Angelantonio, Emanuele; Assimes, Themistocles L.; Bottinger, Erwin P.; Chambers, John C.; Clarke, Robert; Palmer, Colin N A; Cubbon, Richard M.; Ellinor, Patrick T.; Ermel, Raili; Evangelou, Evangelos; Franks, Paul W.; Grace, Christopher; Gu, Dongfeng; Hingorani, Aroon D.; Howson, Joanna M. M.; Ingelsson, Erik; Kastrati, Adnan; Kessler, Thorsten; Kyriakou, Theodosios ; Lehtimäki, Terho; Lu, Xiangfeng; Lu, Yingchang; März, Winfried; McPherson, Ruth; Metspalu, Andres; Pujades-Rodriguez, Mar; Ruusalepp, Arno; Schadt, Eric E.; Schmidt, Amand F; Sweeting, Michael J; Zalloua, Pierre A.; AlGhalayini, Kamal; Keavney, Bernard D.; Kooner, Jaspal S.; Loos, Ruth J. F.; Patel, Riyaz S; Rutter, Martin K; EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group .

In: Nature Genetics, Vol. 49, No. 9, 09.2017, p. 1385-1391.

Research output: Contribution to journalLetter

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 T.

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 - EPIC-CVD Consortium, CARDIoGRAMplusC4D, The UK Biobank CardioMetabolic Consortium CHD working group

N1 - P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project. E.I. is an advisor and consultant for Precision Wellness, Inc., and an advisor for Cellink for work unrelated to the present project. M.K.R. has acted as a consultant for GSK, Roche, Ascensia and MSD and participated in advisory board meetings on their behalf. M.K.R. has received lecture fees from MSD and grant support from Novo Nordisk, MSD and GSK. J.L.M.B. is the founder and chairman of Clinical Gene Networks. CGN has financially contributed to the STARNET study. J.L.M.B., E.E.S. and A.R. are on the board of directors for CGN. J.L.M.B. and A.R. own equity in CGN and receive financial compensation from CGN.

PY - 2017/9

Y1 - 2017/9

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; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 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; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 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.

KW - Journal article

KW - Cardiovascular diseases

KW - Genetics

KW - Genome-wide association studies

KW - Genome-wide association studies

U2 - 10.1038/ng.3913

DO - 10.1038/ng.3913

M3 - Letter

VL - 49

SP - 1385

EP - 1391

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -

Nelson CP, Goel A, Butterworth AS, Kanoni S, Webb TR, Marouli E et al. Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nature Genetics. 2017 Sep;49(9):1385-1391. https://doi.org/10.1038/ng.3913