Variation in CACNA1C has consistently been associated with psychiatric disease in genome-wide association studies. We have previously shown that healthy carriers of the CACNA1C rs1006737 risk variant exhibit hippocampal and perigenual anterior cingulate (pgACC) dysfunction during episodic memory recall. To test whether this brain systems-level abnormality is a potential intermediate phenotype for psychiatric disorder, we studied unaffected relatives of patients with bipolar disorder, major depression, and schizophrenia.
The study population comprised 188 healthy first-degree relatives of patients with bipolar disorder (n = 59), major depression (n = 73), and schizophrenia (n = 56) and 110 comparison subjects from our discovery study who were genotyped for rs1006737 and underwent functional magnetic resonance imaging while performing an episodic memory task and psychological testing. Group comparisons were analyzed using SPM8 and PASW Statistics 20.
Similar to risk allele carriers in the discovery sample, relatives of index patients exhibited hippocampal and pgACC dysfunction as well as increased scores in depression and anxiety measures, correlating negatively with hippocampal activation. Carrying the rs1006737 risk variant resulted in a stronger decrease of hippocampal and pgACC activation in relatives, indicating an additive effect of CACNA1C variation on familial risk.
Our findings implicate abnormal perigenual and hippocampal activation as a promising intermediate phenotype for psychiatric disease and suggest a pathophysiologic mechanism conferred by a CACNA1C variant being implicated in risk for symptom dimensions shared among bipolar disorder, major depression, and schizophrenia.
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Published online: December 09, 2013
Accepted: November 22, 2013
Received in revised form: November 21, 2013
Received: July 16, 2013
Authors SE and AM-L contributed equally to this work.
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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- Imaging Genetics Approaches to Identify Mechanisms in Severe Mental IllnessBiological PsychiatryVol. 76Issue 6
- PreviewSchizophrenia, bipolar disorder, and major depressive disorders are heritable serious mental illnesses (SMI). What does this heritability mean? What are the underlying mechanisms? Large genome-wide association studies (GWAS) have identified both shared and unique genetic risk variants for these disorders; however, causal risk variants, their molecular mechanisms, and their effects on brain circuitry are mostly unknown. Targeted, possibly individualized, therapies addressing underlying mechanisms offer the promise of improved functioning and well-being for patients.