What is CACNA1C?
Bipolar disorder and schizophrenia are known to be highly heritable, with individual heritability estimated to be 70-90% and 80-85%, respectively. In the search for specific markers for these diseases much attention has been paid to the CACNA1C gene. CACNA1C encodes the αalpha 1 subunit of the L-Type voltage-gated Ca2+ channel. It is highly expressed in the heart and brain, where it mediates the influx of calcium ions.1 In this paper, we review the data behind this gene and its association with risk of psychiatric illness and treatment response.
Is CACNA1C a risk factor for bipolar disorder and schizophrenia?
The CACNA1C gene is one of the most highly replicated disease markers in psychiatry. Functional studies have linked genetic variation in this locus to spatial working memory2, emotional lability3, verbal fluency4, and limbic function1,5-10. The gene was first linked to bipolar disorder in 2007 in a genome-wide association study (GWAS) by the Wellcome Trust Case Control Consortium, finding an overrepresentation of rs1006737 in the bipolar cases versus controls.12 Since then, a number of GWAS and other large studies have confirmed this finding.11-23 Other studies have strongly linked CACNA1C to schizophrenia18,23-30 (p = 2.4×10-17 in one meta-analysis31). At this point in time, there is no more highly associated marker for disease risk within the field of psychiatry.
What is the clinical significance of CACNA1C genotyping?
The actual level of risk conferred by CACNA1C variants is very small. For example, the aforementioned meta-analysis in schizophrenia determined the pooled odds ratio for the rs1006737 SNP to be 1.12,31 corresponding to a relative risk of 13%. This indicates that individuals carrying the marker have a 13% increased likelihood of a schizophrenia diagnosis compared to non-carriers. Given a lifetime schizophrenia prevalence of 1.5%32, carriers would be expected to have a 1.7% risk of lifetime schizophrenia diagnosis, compared to a 1.4% risk for non-carriers. In effect, the CACNA1C variant confers a 0.3% absolute increase in risk of developing schizophrenia. Thus, while the diagnostic association appears to be consistent, the absolute contribution of CACNA1C to disease risk is small. This bolsters a concern that clinicians will “overvalue” the modest clinical impact of the variant, resulting in potentially inappropriate use of antipsychotic and mood stabilizing medications.
What do the data say about CACNA1C variation and treatment response?
No data on CACNA1C variants and psychiatric treatment response, including mood stabilizers, antipsychotics and antidepressants, have been published to date (i.e. there is no psychiatric pharmacogenomic data on this gene). Two studies, each on a different CACNA1C polymorphism, have been performed evaluating CACNA1C variation and response to cardiovascular medications.33,34 Well-designed, independently replicated pharmacogenomic studies are needed to determine if CACNA1C variation predicts treatment response to mood stabilizing or antipsychotic agents.
CACNA1C displays a consistent, though very modest, disease association with bipolar disorder and schizophrenia. There is no published data on the gene and medication response for any psychiatric medication. Due to these findings, testing for CACNA1C should not be considered a pharmacogenomic marker and raises important concerns about reasonable thresholds for a molecular diagnostic test in psychiatry. Patients and clinicians who lack a good understanding of the limitations of these data may place undue emphasis on the implications of a positive result, resulting in the potential for misdiagnosis and unnecessary use of antipsychotic or mood stabilizing medications. While CACNA1C remains an intriguing research target, clinical genetic testing for CACNA1C is not recommended at this time.
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