Trio-based pathway analysis of bipolar disorder. N. Matoba1,2, M. Kataoka1,3, K. Fujii4, Y. Suzuki2, S. Sugano2, T. Kato1 1) Lab. for Molecular Dynamics of Mental Disorder, RIKEN Brain Science Institute, Wako , Saitama, Japan; 2) Dept. of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan; 3) Dept. of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo, Japan; 4) Dept. of Psychiatry, Dokkyo Medical University, Mibu, Tochigi, Japan.
Bipolar disorder is one of the two major mental disorders and twin studies reported the heritability is around 85%( Cardno et al., 1999, McGuffin et al., 2003). Genome-Wide Association Studies (GWAS) identified a number of common SNPs that are associated with bipolar disorder, but no strong contribution has been shown. Next-Generation Sequencing (NGS) technology enables us to detect causes of rare genetic disorders. However, the way to identify causative genes of complex diseases like bipolar disorder is still under development. To identify molecular pathways related to bipolar disorder, we compared the deleterious mutations transmitted to, or un-transmitted to the proband using whole exome sequencing of trio families of bipolar disorder. Fifty trio families were enrolled. Each individuals was interviewed by trained psychiatrists using a structured interview were selected. After target exome were captured from the whole-blood or saliva DNA of participants using the SureSelect Human All Exon V4(Agilent), whole-exome sequencing was carried out using Hiseq2000(Illumina). Reads were mapped to human genome build v37 with BWA and PCR duplicates were removed with Picards. Local re-alignment and variant calling was performed using GATK. All variants were annotated with ANNOVAR. 87.8% of target regions were covered with at least 20 unique reads and we only focused on these regions. The criteria for candidate variants were non-synonymous SNVs, not in dbSNP137(excluding MAF < 0.01 or reported as disease related) and predicted as disease causing by SIFT and possibly damaging or probably damaging by PolyPhen2. All variants observed in each family were divided into two groups, transmitted (found in a proband and one of the parents) or un-transmitted (found in a parent only) variants. In a preliminary analysis of 7 families, 42.86 variants were transmitted to proband and 49.29 variants were un-transmitted to the proband on average. Gene Ontology (GO) term GO:0012502 (induction of programmed cell death) was enriched in transmitted variants while muscle development related GO terms were enriched in un-transmitted variants. Enrichment of apoptosis related genes in transmitted mutations is compatible with the possible role of cellular valunevability in bipolar disorder. Further analysis using other 43 trio families with bipolar disorder and control trio families is ongoing.
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