Genome-wide association studies (GWAS) have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). Almost all of these loci have been identified with major contributions of members of the IIEG.
Here, a study co-led by Ingrid Br nne from the IIEG together with colleagues from the CADgenomics network, funded by the Leducq fondation, now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes. They conclude that the great majority of causal variations affecting CAD risk occur in noncoding regions, with 41% affecting gene expression robustly versus 6% leading to amino acid changes. Interestingly, many of these genes differed from the traditionally annotated genes, which was usually based on proximity to the lead single-nucleotide polymorphism. Indeed, the study obtained evidence that genetic variants at CAD loci affect 98 genes, which had not been linked to CAD previously. However, for a full understanding, each CAD locus will have to be individually investigated using tools, such as experimental organisms and iPS cells. In this study, they have used standard tools to refine the list of candidate genes. Additional approaches that could be useful at present include chromosome conformation analyses, application of novel algorithms for causal SNP analysis, network analyses, and identification of rare variants. Looking forward, new resources and tools, such as noncoding RNA annotation, RNA-binding maps, splicing variants and code annotation, and detailed enhancer and transcription maps in a variety of cell types relevant to atherosclerosis, will greatly assist such efforts. The members of the IIEG are well prepared to be part of these endeavours.
Prediction of Causal Candidate Genes in Coronary Artery Disease Loci.
Ingrid Brænne*, Mete Civelek*, Baiba Vilne*, Antonio Di Narzo, Andrew D. Johnson, Yuqi Zhao, Benedikt Reiz, Veronica Codoni, Thomas R. Webb, Hassan Foroughi Asl, Stephen E. Hamby, Lingyao Zeng, David-Alexandre Trégouët, Ke Hao, Eric J. Topol, Eric E. Schadt, Xia Yang, Nilesh J. Samani, Johan L.M. Björkegren, Jeanette Erdmann, Heribert Schunkert†, Aldons J. Lusis†, on behalf of the Leducq Consortium CAD Genomics‡
Arterioscler Thromb Vasc Biol 2015; first published on August 20 2015 as doi:10.1161/ATVBAHA.115.306108
*denotes equal contribution
Members of the CADgenomics network funded by the Leducq fondation
San Diego, February 2015