Mood Disorder Susceptibility Gene Cacna1c Modifies Mood-related Behaviors In Mice And Interacts With Sex To Influence Behavior In Mice And Diagnosis In Humans

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

Background: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis. Methods: 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 ϫ 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). Results: 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 ϭ 1.64, 1.32) but not in male subjects (odds ratio ϭ .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p ϭ 1.4 ϫ 10Ϫ4, 2.1 ϫ 10Ϫ4; pcorrected ϭ .03, .04) and were consistent across two large datasets. Conclusions: 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.


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February 1, 2022