Discovery of gene-gene interactions across multiple independent datasets of Late Onset Alzheimer Disease from the Alzheimer Disease Genetics Consortium

Abstract

Late-onset Alzheimer disease (LOAD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance and gene-gene interactions; however, the investigation of interactions in recent GWAS has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across thirteen datasets from the Alzheimer Disease Genetics Consortium. Fifteen SNP-SNP pairs within three gene-gene combinations were identified: SIRT1 x ABCB1, PSAP x PEBP4, and GRIN2B x ADRA1A. Additionally, we extend a previously identified interaction from an endophenotype analysis between RYR3 x CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this manuscript highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.