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

Molecular Psychiatry volume 20, pages 162–169 (2015)Cite this article

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A Corrigendum to this article was published on 27 January 2015

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.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (R01-MH091115, RF1-AG042978, R01-NS051874 and R01-NS078839 to LHT; MH09395 and MH10028 to RP; R21MH099448-01 to JQP), and the Stanley Medical Research Institute (to LHT, JQP and JMM).

Author Contributions

TY, JQP, JMM and LHT conceived and designed the study; TY, JQP, JMM, AEM and LHT wrote the manuscript; TY and JMM developed the iN protocol. TY conducted immunocytochemistry and qPCR; JQP and SS conducted electrophysiology; AEM conducted qPCR; TY, AEM and JK created lentivirus and cultured iN cells; OD, DM and JMM facilitated the collection of human fibroblasts; JMM confirmed the genotypes. RP and BC provided patient fibroblasts.

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Author notes

  1. T Yoshimizu, J Q Pan and A E Mungenast: These authors contributed equally to this work.

Authors and Affiliations

  1. Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA

    T Yoshimizu, A E Mungenast, S Su & L-H Tsai

  2. Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA,

    T Yoshimizu, A E Mungenast, S Su & L-H Tsai

  3. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA

    J Q Pan, J M Madison, J Ketterman & R Perlis

  4. McLean Hospital and Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    D Ongur, D McPhie & B Cohen

  5. Bipolar Clinic and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    R Perlis

  6. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA

    L-H Tsai

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  1. T Yoshimizu
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Correspondence to J Q Pan or L-H Tsai.

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Yoshimizu, T., Pan, J., Mungenast, A. et al. Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons. Mol Psychiatry 20, 162–169 (2015). https://doi.org/10.1038/mp.2014.143

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