Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans

David T Dao; Pamela Belmonte Mahon; Xiang Cai; Colleen E Kovacsics; Robert A Blackwell; Michal Arad; Jianxin Shi; Peter P Zandi; Patricio O'Donnell; James A Knowles; Myrna M Weissman; William Coryell; William A Scheftner; William B Lawson; Douglas F Levinson; Scott M Thompson; James B Potash; Todd D Gould; Bipolar Disorder Genome Study (BiGS) Consortium

doi:10.1016/j.biopsych.2010.06.019

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Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans

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Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans

David T Dao, Pamela Belmonte Mahon, Xiang Cai, Colleen E Kovacsics, Robert A Blackwell, Michal Arad, Jianxin Shi, Peter P Zandi, Patricio O'Donnell, James A Knowles, …

Biological psychiatry (1969), Vol.68(9), pp.801-810

2010

DOI: 10.1016/j.biopsych.2010.06.019

PMCID: PMC2955812

PMID: 20723887

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Abstract

Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca v1.2, with a bipolar disorder and depression diagnosis. The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms ( p = 1.4 × 10 −4, 2.1 × 10 −4; p corrected = .03, .04) and were consistent across two large datasets. Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.

Animal model

bipolar disorder

Ca V1.2

gender

CACNA1C

major depression

sex differences

Details

Title: Subtitle: Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans
Creators: David T Dao - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
Pamela Belmonte Mahon - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
Xiang Cai - Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland
Colleen E Kovacsics - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
Robert A Blackwell - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
Michal Arad - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
Jianxin Shi - Department of Psychiatry, Stanford University, Palo Alto, California
Peter P Zandi - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
Patricio O'Donnell - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
James A Knowles - Department of Psychiatry, University of Southern California, Los Angeles, California
Myrna M Weissman - Department of Psychiatry, Columbia University, New York, New York
William Coryell - Department of Psychiatry, University of Iowa, Iowa City, Iowa
William A Scheftner - Department of Psychiatry, Rush University Hospital, Chicago, Illinois
William B Lawson - Department of Psychiatry and Behavioral Sciences, Howard University, Washington, District of Columbia
Douglas F Levinson - Department of Psychiatry, Stanford University, Palo Alto, California
Scott M Thompson - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
James B Potash - Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
Todd D Gould - Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland
Bipolar Disorder Genome Study (BiGS) Consortium
Resource Type: Journal article
Publication Details: Biological psychiatry (1969), Vol.68(9), pp.801-810
DOI: 10.1016/j.biopsych.2010.06.019
PMID: 20723887
PMCID: PMC2955812
NLM abbreviation: Biol Psychiatry
ISSN: 0006-3223
eISSN: 1873-2402
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: MH078151, MH059542, MH059552, MH061686, K24MH64197, MH059541, MH060912; DOI: 10.13039/100000025, name: National Institute of Mental Health, award: MH60866
Language: English
Date published: 2010
Academic Unit: Psychiatry
Record Identifier: 9984003976102771

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