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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; 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 GWAS2,3. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold2, 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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Figure 1: Description of HARD and SOFT CAD phenotypes in UK Biobank.
Figure 2: Transposed Manhattan plot showing meta-analysis results for the SOFT CAD definition under an additive model.
Figure 3: Comparison of single-marker P values for the 5% FDR variants in the published CARDIoGRAMplusC4D 1000 Genomes–imputed CAD GWAS meta-analysis and the current FDR-based analysis.
Figure 4: Heat map showing DEPICT gene set enrichment results with zoom-in on a subset of the results.

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Acknowledgements

This work was funded by British Heart Foundation (BHF) grants RG/14/5/30893 to P.D. and FS/14/66/31293 to O.G. The work of P.D. forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre and Leicester Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). F.Y.L. and S.E.H. are funded by NIHR. C.P.N., T.R.W. and N.J.S. are funded from BHF, the Transatlantic Networks of Excellence Award (12CVD02) from the Leducq Foundation and EU-FP7/2007-2013 grant HEALTH-F2-2013-601456. N.J.S. is an NIHR Senior Investigator. PROCARDIS was supported by EU-FP6 (LSHM-CT- 2007-037273), AstraZeneca, BHF, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, Karolinska Institutet, Foundation Strategic Research and the Stockholm County Council (560283). M.F. and H.W. are supported by Wellcome Trust award 090532/Z/09/Z, and M.F., H.W. and T.K. are supported by the BHF Centre of Research Excellence. A.G., H.W. and T.K. are supported by FP7/2007-2013 (HEALTH-F2-2013-601456 (CVGenes@Target)), and A.G. is supported by the Wellcome Trust and the TriPartite Immunometabolism Consortium-Novo Nordisk Foundation (NNF15CC0018486). HPS (ISRCTN48489393) was supported by the Medical Research Council (MRC), BHF, Merck and Co, and Roche Vitamins, Ltd. HPS acknowledges National Blood Service donor and UK-Twin Study controls (Wellcome Trust 07611, FP7/2007-2013). J.C.H. is funded by BHF (FS/14/55/30806). The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. The GLACIER Study and P.W.F. are funded by the European Commission (CoG-2015_681742_NASCENT), the Swedish Research Council (Distinguished Young Researchers Award), the Heart-Lung Foundation and the Novo Nordisk Foundation. OHGS studies were funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Heart & Stroke Foundation of Canada. LURIC was funded from the EU-FP7 (Atheroremo (201668), RiskyCAD (305739), INTERREG IV Oberrhein Program), the European Regional Development Fund (ERDF), Wissenschaftsoffensive TMO and from the German Ministry for Education and Research, project e:AtheroSysMed (01ZX1313A-K). LOLIPOP is supported by the NIHR-BRC Imperial College Healthcare NHS Trust, BHF (SP/04/002), MRC (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), NIHR (RP-PG-0407-10371), EU-FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The Helsinki Sudden Death Study was funded by EU-FP7 (201668, AtheroRemo), the Tampere University Foundation, Tampere University Hospital Medical Funds (grants 9M048 and 9N035 for T.L.), the Emil Aaltonen Foundation (T.L.), the Finnish Foundation of Cardiovascular Research (T.L., P.K.), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Tampere Tuberculosis Foundation (T.L.), the Signe and Ane Gyllenberg Foundation (T.L.) and the Diabetes Research Foundation of the Finnish Diabetes Association (T.L.). M.T. (PG/16/49/32176) and R.C. (FS/12/80/29821) are supported by BHF. E.Z. acknowledges Wellcome Trust funding (098051). H.S. was supported by Deutsche Forschungsgemeinschaft (Sonderforschungsbereich CRC 1123 (B02)). The MRC/BHF Cardiovascular Epidemiology Unit was funded by MRC (G0800270), BHF (SP/09/002), NIHR-BRC Cambridge, the European Research Council (ERC; 268834), EU-FP7 (HEALTH-F2-2012-279233), Pfizer, Merck and Biogen. EPIC-CVD was supported by the University of Cambridge, EU-FP7 (HEALTH-F2-2012-279233), MRC (G0800270), BHF (SP/09/002) and ERC (268834). We thank all EPIC participants and staff and S. Spackman. EGCUT was funded by the Estonian Research Council grant for data management and the EPIC-CVD Coordinating Centre team. (IUT20-60), the Centre of Excellence in Genomics and Translational Medicine (GENTRANSMED), EU structural fund (Archimedes Foundation; 3.2.1001.11-0033), PerMed I and EU2020 (692145 ePerMed). This research was supported by BHF (SP/13/2/30111) and conducted using the UK Biobank Resource (application number 9922).

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C.P.N., A.G., A.S.B., S.K., T.R.W., E.M., I.N., J.C.H., O.G., H.S., M.F., J.D., N.J.S., H.W. and P.D. wrote and edited the manuscript. All authors contributed and discussed the results and commented on the manuscript. A.S.B., O.G., T.J., L.Z., S.E.H., E.A., T.L.A., E.P.B., J.C.C., R.C., R.M.C., P.E., R.E., E.E., P.W.F., C.G., D.G., A.H., J.M.M.H., E.I., A.K., T. Kessler, T. Kyriakou, T.L., X.L., Y.L., W.M., R.M., A.M., C.N.A.P., M.P.-R., A.F.S., M.J.S., P.A.Z., K.A., R.J.F.L., E.Z., J.E., G.D., H.S., J.D., N.J.S., H.W. and P.D. generated data and cohorts. C.P.N., A.S.B., I.N., F.Y.L., J.C.H., O.G., B.D.K., J.S.K., R.J.F.L., R.S.P., M.R., M.T., I.T., E.Z., J.E., G.D., H.S., J.D., N.J.S., H.W. and P.D. analyzed phenotype data for UKBB and replication studies. C.P.N., A.G., A.S.B., S.K., T.J. and M.F. performed the statistical analyses. C.P.N., S.K., T.R.W., A.S.B., R.E., A.R., E.E.S. and J.L.M.B. performed functional annotation. E.M. and P.D. performed biological and clinical enrichment and pathway analyses.

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Correspondence to Hugh Watkins.

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Competing interests

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.

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Nelson, C., Goel, A., Butterworth, A. et al. Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nat Genet 49, 1385–1391 (2017). https://doi.org/10.1038/ng.3913

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