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

Area of Science:

• Genetics
• Cardiovascular Disease Research

Background:

• Genome-wide association studies (GWAS) have identified numerous genetic loci for coronary artery disease (CAD).
• The false discovery rate (FDR) approach offers a method to identify additional putative loci beyond genome-wide significance thresholds.
• The validity of the FDR approach in CAD genetics requires further evaluation.

Purpose of the Study:

• To evaluate the validity of the false discovery rate (FDR) approach for identifying genetic loci associated with coronary artery disease (CAD).
• To leverage UK Biobank (UKBB) data to test the FDR approach in a large-scale CAD meta-analysis.

Main Methods:

• Utilized an interim release of UK Biobank (UKBB) data for a large-scale CAD meta-analysis.
• Tested two CAD phenotypes: inclusive of angina (SOFT) and a stricter definition without angina (HARD).
• Conducted meta-analysis using two recent CAD GWAS, focusing on cases with the SOFT phenotype.

Main Results:

• Identified 13 new loci associated with CAD at genome-wide significance.
• 12 of the 13 new loci were previously identified using the 5% FDR threshold, strongly supporting the FDR approach.
• 304 independent variants at 5% FDR explained 21.2% of CAD heritability, implicating pathways in blood vessel morphogenesis, lipid metabolism, nitric oxide signaling, and inflammation.

Conclusions:

• The FDR approach is a valid and powerful method for identifying genuine genetic loci associated with coronary artery disease.
• This study significantly expands the number of known CAD risk loci and associated biological pathways.
• Findings provide a foundation for further research into the genetic architecture and molecular mechanisms of CAD.