Abstract 10455: Single Marker and Pathway Analysis of Genome Wide Association Data From Premature Coronary Artery Cases of Northern European Descent (Ottawa Heart Genomics Study)
Background: Although genome wide association studies (GWAS) have been highly successful at identifying novel genetic loci associated with coronary artery disease (CAD), traditional single marker analysis ignores many moderately associated SNPs during multiple testing corrections. Pathway based analyses can be useful in uncovering pathways consisting of genes for which no individual SNP satisfies a traditional genome wide significant p-value threshold, but for which there exists an excess of variants with low to moderate effect on the disease.
Methods: Genotyping was carried out on Affymetrix 500K, 6.0 or Axiom arrays over 4 independent studies involving 5,085 cases of premature CAD (mean age 47.8 years) and 3,558 elderly, unaffected controls (mean age 74.9 years). Each study was separately imputed using 1000 Genomes, with SNP selection as follows: MAF>1%, HWE<1e-6, call rate > 90%, info >0.8. Single marker association analysis was carried out for each study via logistic regression after adjusting for gender and the first two principal components of ancestry.
Results were combined using an inverse-variance fixed-effects genomic-control meta-analysis, resulting in 5,131,673 retained SNPs with low genomic inflation (lambda = 1.024). Pathway analysis was carried out using multiple tools such as DAVID and iGSEA4GWAS. A gene wide p-value was obtained from the most significant p-value of all SNPs belonging to the gene.
Results: SNP rs7859362, adjacent to CDKN2A and CDKN2B in the 9p21 region, was identified as the top CAD-associated SNP in the meta-analysis of single markers (p<2.87e-22). Pathway analysis in DAVID identified pathways related to cardiomyopathy, focal adhesion, cadherin and Wnt signaling as being enriched in gene variants associated with CAD (p<1e-3). Analysis using iGSEA4GWAS identified additional enrichment in pathways related to immune-inflammation (p<1e-3).
Conclusion: The strong association of rs7859362 with CAD is consistent with earlier findings. Pathway analysis further identified several candidate biological mechanisms that could be related to CAD via enrichment of genetic variants of moderate to low effects and may provide new information relevant to the complex genetic architecture of coronary artery disease.
- © 2011 by American Heart Association, Inc.