Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans

Biol Psychiatry. 2010 Nov 1;68(9):801-10. doi: 10.1016/j.biopsych.2010.06.019. Epub 2010 Aug 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium Channels, L-Type / genetics*
  • Dextroamphetamine / pharmacology
  • Disease Models, Animal
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Haploinsufficiency
  • Heterozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mood Disorders / diagnosis*
  • Mood Disorders / genetics*
  • Polymorphism, Single Nucleotide
  • Sex Characteristics

Substances

  • CACNA1C protein, human
  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Dextroamphetamine

Grant support