Integrating biological information in genome-wide association interaction (GWAI) studies.

Genome-wide association (GWA) studies of Crohn's disease have identified numerous genes. However, a substantial portion of the heritability of this disease remains unexplained. Some gene variants, not detectable via main effects GWA study, may manifest themselves only in interaction with other variants. To search for interacting genes involved in the regulation of Crohn's disease, we performed GWA epistasis screening in a large human cohort (1851 cases/2938 controls) belonging to the Wellcome Trust Case Control Consortium (WTCCC). All subjects were genotyped with the GeneChip 500K Mapping Array Set (Affymetrix chip). SNPs that passed our quality control (359,479 SNPs) were processed in Biofilter (a software package that looks for candidate epistatic genes contributing to disease risk) giving rise to 14,185 SNPs. Subsequent MB-MDR epistasis screening, highlighted evidence for statistical epistasis for 6 SNP pairs. Four of these pairs involve interaction on between the HTR3B and USP28 genes (chromosome 11). One pair involves an interaction between the SLED1 and ACSL1 genes (chromosome 4). Another pair involves an interaction between PTPN22 (chromosome 1) and a SNP located between USPL1 and ALOX5AP (chromosome 13). Notably, when mapped to the same genomic regions, the interacting SNPs were not in linkage disequilibrium (r^2 < 0.11). All results were corrected for potential main SNP effects and were corrected for multiple testing on 7072 SNPs (i.e., 25,003,056 pairs). We investigated the consistency of these findings using different methodologies, including information-based, LD comparison-based and regression-based approaches. We also investigated the utility of using prior information from biological interaction data bases in novel epistasis discoveries, as well as the utility of biological data bases in interpreting a posterior identified statistical epistasis pairs. Our findings may provide new leads on important pathways involved in Crohn's disease.