SA10 - USING WHOLE GENOME SEQUENCING TO IDENTIFY DE NOVO VARIATION IN BIPOLAR DISORDER

Abstract

Background Although most gene-discovery efforts in Bipolar Disorder (BD) have focused on inherited variation, the association of BD with increased paternal age and prior association of de novo copy-number variants with BD, suggests that de novo mutations may also play a role. Methods We have performed deep whole genome sequencing of 97 trios selected specifically to have no family history of bipolar disorder. Diagnoses were based on the Diagnostic Instrument for Genetics Studies with two independent best-estimate evaluations. Sequencing was performed on Illumina Hi-Seq with an average depth of 37X. Variant calling was performed according using the GATK using haplotype caller and best-practice recommendations. De novo calls were individually visualized with the Integrative Genomics Viewer and a subset, including all exonic variation, underwent confirmatory Sanger sequencing. Results We identified 6,882 de novo variants throughout the genome, representing an average of 73.3 de novo Single Nucleotide Variants (SNVs) and indels per family (range 43 -106). As expected, the number of de novo variants correlated strongly with paternal age (P Discussion Our whole genome study of de novo variation provides initial evidence for an association of disruptive mutations in highly conserved genes with BD. The consistency of our results with the only other study of de novo variation in BD highlights the need for further study of de novo variation in BD.