Abstract MP57: Pathway and Network Analysis of GWAS reveals Novel Candidate Causal Links between Key Biological Processes and Coronary Artery Disease

Abstract

Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, for most of these variants the causal biological mechanisms remain unclear. By integrating GWA data with prior biological knowledge about pathways and functional networks, we sought to obtain novel insights into the causal processes of CAD. Using the iGSEA4GWAS analysis tool and the Reactome pathway database, we carried out a two-stage gene set enrichment analysis strategy. From a discovery cohort of seven large GWAS data sets for CAD (n=9,889 cases, 11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of nine additional studies (n=15,502 cases, 55,730 controls) that were part of the CARDIoGRAM Consortium. A total of 32 of the 639 pathways tested representing 22 distinct biological processes showed convincing association with CAD (replication p< 0.05). After adjusting for redundancies by removing pathways with 50% or greater identity with other pathways, 19 pathways representing 9 biological processes remained including those relevant to Notch signaling, extracellular matrix integrity, innate immunity, and lipid metabolism. Network analysis of 751 unique genes within replicated pathways further revealed several interconnected functional modules representing novel associations (semaphorin regulated axonal guidance pathway) as well as confirmatory known processes (lipid metabolism). Our analyses point to potentially novel causal associations between CAD and several biological processes, many of which were not previously linked to CAD. These findings improve our understanding of the biological basis of CAD and highlight potential novel therapeutic targets.