Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons
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Tsai_Functional implications.pdf
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Author(s)
Yoshimizu, Takao
Pan, Jen Q.
Mungenast, Alison
Madison, Jon Morrow
Su, S.
Ketterman, Joshua
Ongur, Dost
McPhie, D.
Cohen, B.
Perlis, Roy H.
Date Issued
November 2014
Journal
Molecular Psychiatry
Publisher
Nature Publishing Group
Citation
Yoshimizu, T, J Q Pan, A E Mungenast, J M Madison, S Su, J Ketterman, D Ongur, et al. “Functional Implications of a Psychiatric Risk Variant Within CACNA1C in Induced Human Neurons.” Mol Psychiatry 20, no. 2 (November 18, 2014): 162–169.
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Author's final manuscript
Abstract
Psychiatric disorders have clear heritable risk. Several large-scale genome-wide association studies have revealed a strong association between susceptibility for psychiatric disorders, including bipolar disease, schizophrenia and major depression, and a haplotype located in an intronic region of the L-type voltage-gated calcium channel (VGCC) subunit gene CACNA1C (peak associated SNP rs1006737), making it one of the most replicable and consistent associations in psychiatric genetics. In the current study, we used induced human neurons to reveal a functional phenotype associated with this psychiatric risk variant. We generated induced human neurons, or iN cells, from more than 20 individuals harboring homozygous risk genotypes, heterozygous or homozygous non-risk genotypes at the rs1006737 locus. Using these iNs, we performed electrophysiology and quantitative PCR experiments that demonstrated increased L-type VGCC current density as well as increased mRNA expression of CACNA1C in iNs homozygous for the risk genotype, compared with non-risk genotypes. These studies demonstrate that the risk genotype at rs1006737 is associated with significant functional alterations in human iNs, and may direct future efforts at developing novel therapeutics for the treatment of psychiatric disease.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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DOI of Published Version
https://doi.org/10.1038/mp.2014.143
