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

Mol Psychiatry. 2015 Feb;20(2):162-9. doi: 10.1038/mp.2014.143. Epub 2014 Nov 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Astrocytes / drug effects
  • Calcium / metabolism
  • Calcium Channel Agonists / pharmacology
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Cell Differentiation / drug effects
  • Coculture Techniques
  • Female
  • Fibroblasts / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins / therapeutic use
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology*
  • Mental Disorders / genetics*
  • Mental Disorders / pathology*
  • Middle Aged
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transduction, Genetic
  • Young Adult

Substances

  • CACNA1C protein, human
  • CACNA1D protein, human
  • Calcium Channel Agonists
  • Calcium Channels, L-Type
  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Transcription Factors
  • Calcium