Association analyses based on false discovery rate implicate new loci for coronary artery disease.
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., EPIC-CVD Consortium None., CARDIoGRAMplusC4D None., UK Biobank CardioMetabolic Consortium CHD working group None., Schunkert H., Farrall M., Danesh J., Samani NJ., Watkins H., Deloukas P.
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.