BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, 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 × 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 = 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. 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.
BACKGROUND: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, 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 × 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 = 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. 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.
Authors: M Wessa; J Linke; S H Witt; V Nieratschker; C Esslinger; P Kirsch; O Grimm; M G Hennerici; A Gass; A V King; M Rietschel Journal: Mol Psychiatry Date: 2010-03-30 Impact factor: 15.992
Authors: M Nyegaard; D Demontis; L Foldager; A Hedemand; T J Flint; K M Sørensen; P S Andersen; M Nordentoft; T Werge; C B Pedersen; D M Hougaard; P B Mortensen; O Mors; A D Børglum Journal: Mol Psychiatry Date: 2010-02 Impact factor: 15.992
Authors: C Seisenberger; V Specht; A Welling; J Platzer; A Pfeifer; S Kühbandner; J Striessnig; N Klugbauer; R Feil; F Hofmann Journal: J Biol Chem Date: 2000-12-15 Impact factor: 5.157
Authors: G Shaltiel; S Maeng; O Malkesman; B Pearson; R J Schloesser; T Tragon; M Rogawski; M Gasior; D Luckenbaugh; G Chen; H K Manji Journal: Mol Psychiatry Date: 2008-03-11 Impact factor: 15.992
Authors: Kole Roybal; David Theobold; Ami Graham; Jennifer A DiNieri; Scott J Russo; Vaishnav Krishnan; Sumana Chakravarty; Joseph Peevey; Nathan Oehrlein; Shari Birnbaum; Martha H Vitaterna; Paul Orsulak; Joseph S Takahashi; Eric J Nestler; William A Carlezon; Colleen A McClung Journal: Proc Natl Acad Sci U S A Date: 2007-03-22 Impact factor: 11.205
Authors: Adem Can; David T Dao; Chantelle E Terrillion; Sean C Piantadosi; Shambhu Bhat; Todd D Gould Journal: J Vis Exp Date: 2012-01-28 Impact factor: 1.355
Authors: Wen Li; Chun Chieh Fan; Tuomo Mäki-Marttunen; Wesley K Thompson; Andrew J Schork; Francesco Bettella; Srdjan Djurovic; Anders M Dale; Ole A Andreassen; Yunpeng Wang Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2018-04-28 Impact factor: 3.568
Authors: Peter S Jensen; Mark A Frye; Joanna M Biernacka; Paul E Croarkin; Joan L Luby; Kelly Cercy; Jennifer R Geske; Marin Veldic; Matthew Simonson; Paramjit T Joshi; Karen Dineen Wagner; John T Walkup; Malik M Nassan; Alfredo B Cuellar-Barboza; Leah Casuto; Susan L McElroy Journal: J Clin Psychiatry Date: 2017 Nov/Dec Impact factor: 4.384