Genetic variation in CACNA1C affects brain circuitries related to mental illness.
BACKGROUND
The CACNA1C gene (alpha-1C subunit of the L-type voltage-gated calcium channel) has been identified as a risk gene for bipolar disorder and schizophrenia, but the mechanism of association has not been explored.


OBJECTIVE
To identify the neural system mechanism that explains the genetic association between the CACNA1C gene and psychiatric illness using neuroimaging and human brain expression.


METHODS
We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure brain activation in circuitries related to bipolar disorder and schizophrenia by comparing CACNA1C genotype groups among healthy subjects. We tested the effect of genotype on messenger RNA (mRNA) levels of CACNA1C in postmortem human brain. A case-control analysis was used to determine the association of CACNA1C genotype with schizophrenia.


METHODS
National Institutes of Health Clinical Center.


METHODS
Healthy men and women of white race/ethnicity participated in the fMRI study. Postmortem samples from normal human brains were used for the brain expression study. Patients with schizophrenia and healthy subjects were used in the case-control analysis.


METHODS
BOLD fMRI, mRNA levels in postmortem brain samples, and genetic association with schizophrenia.


RESULTS
The risk-associated single-nucleotide polymorphism (SNP rs1006737) in CACNA1C predicted increased hippocampal activity during emotional processing (P = .001 uncorrected, P((false recovery rate [FDR])) = .05, z = 3.20) and increased prefrontal activity during executive cognition (P = 2.8e-05 uncorrected, P(FDR) = .01, z = 4.03). The risk-associated SNP also predicted increased expression of CACNA1C mRNA in human brain (P = .002). CACNA1C was associated with schizophrenia in our case-control sample (odds ratio, 1.77; P = .03).


CONCLUSIONS
The risk-associated SNP in CACNA1C maps to circuitries implicated in genetic risk for bipolar disorder and schizophrenia. Its effects in human brain expression implicate a molecular and neural system mechanism for the clinical genetic association.
Bigos
Kristin L
KL
Genes, Cognition, and Psychosis Program, Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Mattay
Venkata S
VS
Callicott
Joseph H
JH
Straub
Richard E
RE
Vakkalanka
Radhakrishna
R
Kolachana
Bhaskar
B
Hyde
Thomas M
TM
Lipska
Barbara K
BK
Kleinman
Joel E
JE
Weinberger
Daniel R
DR
D000328:Adult; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009434:Neural Pathways / Q000378:metabolism / Q000503:physiopathology; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger; D010100:Oxygen
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