Original Research ARTICLE
Rare genomic variants link bipolar disorder with anxiety disorders to CREB-regulated intracellular signaling pathways
- 1Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA
- 2Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, USA
- 3Golden Helix, Bozeman, MT, USA
- 4Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- 5Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA
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.
Keywords: bipolar disorder, exome sequencing, genetic risk factors, rare-variant common-disease model, ERK/MAPK and CREB-regulated intracellular signaling pathway, stress response, neuronal plasticity, threshold disease model
Citation: Kerner B, Rao AR, Christensen B, Dandekar S, Yourshaw M and Nelson SF (2013) Rare genomic variants link bipolar disorder with anxiety disorders to CREB-regulated intracellular signaling pathways. Front. Psychiatry 4:154. doi: 10.3389/fpsyt.2013.00154
Received: 27 August 2013; Paper pending published: 03 October 2013;
Accepted: 09 November 2013; Published online: 28 November 2013.
Edited by:Ming D. Li, University of Virginia, USA
Reviewed by:Konrad Prasad, University of Pittsburgh School of Medicine, USA
Jaanus Harro, University of Tartu, Estonia
Copyright: © 2013 Kerner, Rao, Christensen, Dandekar, Yourshaw and Nelson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Berit Kerner, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, 760 Westwood Plaza, Room 47-355A, Los Angeles, CA 90095, USA e-mail: firstname.lastname@example.org