3 years ago

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

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

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.

Publisher URL: http://dx.doi.org/10.1038/ng.3913

DOI: 10.1038/ng.3913

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