title: Rare deleterious mutations are associated with disease in bipolar disorder families.
abstract: Bipolar disorder (BD) is a common, complex and heritable psychiatric disorder characterized by episodes of severe mood swings. The identification of rare, damaging genomic mutations in families with BD could inform about disease mechanisms and lead to new therapeutic interventions. To determine whether rare, damaging mutations shared identity-by-descent in families with BD could be associated with disease, exome sequencing was performed in multigenerational families of the NIMH BD Family Study followed by in silico functional prediction. Disease association and disease specificity was determined using 5090 exomes from the Sweden-Schizophrenia (SZ) Population-Based Case-Control Exome Sequencing study. We identified 14 rare and likely deleterious mutations in 14 genes that were shared identity-by-descent among affected family members. The variants were associated with BD (P<0.05 after Bonferroni's correction) and disease specificity was supported by the absence of the mutations in patients with SZ. In addition, we found rare, functional mutations in known causal genes for neuropsychiatric disorders including holoprosencephaly and epilepsy. Our results demonstrate that exome sequencing in multigenerational families with BD is effective in identifying rare genomic variants of potential clinical relevance and also disease modifiers related to coexisting medical conditions. Replication of our results and experimental validation are required before disease causation could be assumed.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Rao
authors.affiliation: Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yourshaw
authors.affiliation: Golden Helix Inc., Bozeman, MT, USA.
authors.forename: B
authors.initials: B
authors.lastname: Christensen
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kerner
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012559:Schizophrenia / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D013548:Sweden