title: Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations.
abstract: Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.|Department of Child Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.|Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Matoba
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sawada
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: A-A
authors.initials: AA
authors.lastname: Kazuno
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishiwata
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.|Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.affiliation: Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takata
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan.
authors.forename: T
authors.identifier: 0000-0001-7856-3952
authors.initials: T
authors.lastname: Kato
mesh_terms: D000293:Adolescent; D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods