Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons.
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.
1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
T
T
Yoshimizu
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
J Q
JQ
Pan
1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
A E
AE
Mungenast
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
J M
JM
Madison
1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA.
S
S
Su
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
J
J
Ketterman
McLean Hospital and Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
D
D
Ongur
McLean Hospital and Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
D
D
McPhie
McLean Hospital and Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
B
B
Cohen
1] Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA [2] Bipolar Clinic and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
R
R
Perlis
1] Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA [2] Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
L-H
LH
Tsai
D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001523:Mental Disorders / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D055815:Young Adult
C079146:CACNA1C protein, human; C472073:CACNA1D protein, human; D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D002118:Calcium