SA27 - EXOME SEQUENCING OF MULTIPLY AFFECTED BIPOLAR DISORDER FAMILIES AND FOLLOW-UP RESEQUENCING IMPLICATE RARE VARIANTS IN NEURONAL GENES CONTRIBUTING TO DISEASE ETIOLOGY

Abstract

Background Bipolar Disorder (BD) is a complex neuropsychiatric disorder characterized by recurrent episodes of mania and depression. It is a severe disorder of mood with a lifetime prevalence of about 1% and a high heritability of about 70%. Models of illness are most consistent with a polygenic contribution of common and rare variants to disease susceptibility. As the cumulative impact of common alleles with small effect may only explain around 25–38% of the phenotypic variance for BD, rare variants of high penetrance have been suggested to contribute to BD susceptibility. One way to evaluate this hypothesis is to investigate large pedigrees densely affected with BD, in which the existence of a genetic variant of strong effect inherited from a common ancestor may be more likely. Methods In the present study, we investigated 226 individuals of 68 large multiply affected families of European origin using Whole Exome Sequencing (WES). In each family, two to five affected individuals with BD or recurrent major depression were selected for sequencing. WES was performed on the Illumina HiSeq. 2500 platform and the Varbank pipeline of the Cologne Center for Genomics was used for data analysis. All identified variants shared within each family were filtered for a minor allele frequency Results We identified a total of 1214 rare, segregating and functional variants implicating 1122 different genes, of which 903 were brain expressed. Subsequently, we applied the Residual Variation Intolerance Scores (Petrovski et al., 2013) and identified 294 genes that were ranked among the 20% most “intolerant” genes in the genome. Gene enrichment analysis of these genes showed a significant enrichment for 18 pathways (p We prioritized genes that were (i) found in at least two unrelated families in the present study, (ii) previously reported in next generation sequencing or GWAS studies of BD, or (iii) predominantly driving the significant pathways in our gene enrichment analysis. The different approaches of prioritization yielded 42 promising candidate genes including CDH22 which encodes a calcium-dependent cell adhesion protein that plays an important role in the morphogenesis of neural cells during brain development. Discussion Our preliminary results strongly suggest that rare and highly-penetrant variants in neuronal and cell adhesion genes contribute to BD etiology. The 42 prioritized candidate genes are currently being followed up by resequencing in cohorts of about 2500 independent BD cases and 2500 controls of European ancestry. For resequencing, we use the single molecule molecular inversion probes (smMIPs) technology that enables multiplex targeted resequencing in large cohorts. The smMIPs sequences have been designed with the empirically trained design algorithm MIPgen (Boyle et al., 2014) and sequencing is currently performed on the Illumina HiSeq. 2500 platform. The resequencing results will provide further insights into the particular genes and pathways which are involved in BD development.