----------------------------------------------------------------------- BIOINFORMATICS COLLOQUIUM College of Science George Mason University ----------------------------------------------------------------------- Contribution of local genetic variants to differential gene expression in the prefrontal cortex of bipolar disorder patients Brandon Higgs Abstract: Genetic variation may contribute to differential gene expression in the brains of psychiatric patients. We investigated the association between genes differentially expressed in the prefrontal cortex (PFC) of bipolar disorder patients and single nucleotide polymorphisms (SNPs) adjacent to those genes. Postmortem brains from bipolar disorder (N=40) and unaffected controls (N=43) were profiled using genome-wide expression and SNP microarrays. We identified 294 genes as being differentially expressed (fold change>1.3 and FDR-adjusted q-value<0.05) in the PFC of bipolar disorder patients. We then identified cis-acting SNPs that were associated with expression of each differentially-expressed gene, using multiple regression models. Finally, we tested association between the cis-acting SNPs and bipolar disorder, using results derived from a meta-analysis of genome-wide association (GWA) studies including 4,936 bipolar disorder and 6,654 unaffected controls. We identified 49 SNPs that were significantly (FDR q-value<0.05) associated with expression of the differentially-expressed transcripts. Expression levels of HBS1L (16 SNPs), HLA-DPB1 (15 SNPs), AMFR (8 SNPs), PCLO (2 SNPs) and WDR41 (2 SNPs) were correlated with multiple cis-acting SNPs. Among the cis-acting SNPs, rs13438494 in an intron of the piccolo (PCLO) gene was significantly associated with bipolar disorder (adj. p<0.05) in the meta-analysis results. These results are consistent with previous findings implicating PCLO in mood disorder and demonstrate the utility of combining data on differential gene expression, genetic variants that control expression and case-control association results in order to enhance our understanding of the genetic contribution to bipolar disorder.