Association analyses based on false discovery rate implicate new loci for coronary artery disease.
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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.
AuthorsNelson, 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; EPIC-CVD Consortium; CARDIoGRAMplusC4D; UK Biobank CardioMetabolic Consortium CHD working group; Schunkert, H; Farrall, M; Danesh, J; Samani, NJ; Watkins, H; Deloukas, P
- Genomic Medicine