46 - THE POLYGENIC EPISTASIS RISK SCORE DEMONSTRATES SIGNIFICANT ROLE OF GENE INTERACTION IN BIPOLAR DISORDER

Abstract

Background Gene-gene interaction occurs when the association of one locus to a phenotype depends on the genotype at a different locus. GWAS has made possible the discovery of dozens of genes for psychiatric illnesses generally using a model in which there is no gene-gene interaction. Even a modest GWAS may include 1 M SNPs, making an exhaustive search for interaction vastly underpowered. Yet, interaction effects are frequently found in defined biological systems, though they may have significant effect sizes, none can survive correction for genome-wide comparisons. Though polygenic models such as the polygenic risk score, achieve high reproducibility, they explain only a small portion of the genetic variance and do not incorporate interaction. A more realistic model is that in addition to a large number of independent marginal effects, there are also a very large number of interaction effects. In order to test this, I propose an extension to the polygenic risk score and demonstrate a significant contribution of gene-gene interaction in bipolar disorder. Methods The 1500 most significant SNPs in the PGCBD1 GWAS were selected for interaction testing. The model dataset was the GAIN bipolar sample of 995 cases and 1,023 controls. The test sample was a similarly collected set of subjects termed the TGEN sample of 1,199 cases and 403 controls. Interactions among these SNPs were detected using a case-case analysis as implemented in the plink –fast epistasis option. A routine was written in R, to estimate the odds ratios of each genotypic combination in each interaction detected. This array of odds ratios was then used to weight the nine genotypic combinations as seen in each individual in the test dataset. The log10 of these odds ratios then were summed over all interactions to produce a cumulative score representing genetic loading due to interactions. This I have termed the Polygenic Epistasis Risk Score (PERS). An R package will be made available. Results 11,605 interactions were detected in the GAIN sample amongst the 1500 SNPs tested that met a criterion of p Discussion The highly significant enrichment of the TGEN sample for interactions found in the GAIN sample argues for a substantial contribution of interaction in bipolar disorder. It also argues for the model of a very large number of interactions of small effect that add or otherwise combine together. This score can be combined with conventional PRS in order to capture a larger portion of the genetic variance and improve the power of such analyses.