title: Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways.
abstract: Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.
authors.affiliation: Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Berit
authors.initials: B
authors.lastname: Kerner
authors.affiliation: Department of Human Genetics, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Aliz R
authors.initials: AR
authors.lastname: Rao
authors.affiliation: Golden Helix , Bozeman, MT , USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Christensen
authors.affiliation: Department of Human Genetics, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Sugandha
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: Department of Human Genetics, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Yourshaw
authors.affiliation: Department of Human Genetics, University of California Los Angeles , Los Angeles, CA , USA ; Department of Psychiatry and Biobehavioral Sciences, 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: Stanley F
authors.initials: SF
authors.lastname: Nelson
keywords: ERK/MAPK and CREB-regulated intracellular signaling pathway; bipolar disorder; exome sequencing; genetic risk factors; neuronal plasticity; rare-variant common-disease model; stress response; threshold disease model