Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.

Mol Psychiatry
Authors
Keywords
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.

Year of Publication
2015
Journal
Mol Psychiatry
Volume
20
Issue
2
Pages
162-9
Date Published
2015 Feb
ISSN
1476-5578
URL
DOI
10.1038/mp.2014.143
PubMed ID
25403839
PubMed Central ID
PMC4394050
Links
Grant list
RF1 AG042978 / AG / NIA NIH HHS / United States
R01 NS051874 / NS / NINDS NIH HHS / United States
R01 MH091115 / MH / NIMH NIH HHS / United States
MH09395 / MH / NIMH NIH HHS / United States
R01 NS078839 / NS / NINDS NIH HHS / United States
MH10028 / MH / NIMH NIH HHS / United States
R01-NS078839 / NS / NINDS NIH HHS / United States
R21 MH099448 / MH / NIMH NIH HHS / United States
R01-NS051874 / NS / NINDS NIH HHS / United States
RF1-AG042978 / AG / NIA NIH HHS / United States
R21MH099448-01 / MH / NIMH NIH HHS / United States
R01-MH091115 / MH / NIMH NIH HHS / United States