rs1006737 — CACNA1C

The Brain's Voltage-Gated Mood Regulator

Your CACNA1C gene encodes the alpha-1C subunit¹¹ alpha-1C subunit
the pore-forming component through which calcium ions flow of L-type voltage-gated calcium channels (Cav1.2) in the brain. These channels act as gatekeepers for calcium influx into neurons during electrical signaling. Calcium isn't just about bones — in the brain, it's a critical second messenger that shapes synaptic plasticity²² synaptic plasticity
the ability of neural connections to strengthen or weaken over time, memory formation, and emotional regulation.

The rs1006737 variant sits in intron 3 of CACNA1C and has emerged as one of the most robustly replicated genetic risk factors for psychiatric disorders across multiple genome-wide association studies³³ genome-wide association studies
GWAS scan millions of genetic variants to find associations with disease. This isn't a rare pathogenic mutation — it's a common variant that subtly tunes calcium channel expression and function, with downstream effects on mood stability, stress resilience, and cognitive processing.

The Mechanism

The rs1006737 SNP is located in a regulatory region that affects CACNA1C gene expression levels rather than altering the protein structure itself. Functional studies⁴⁴ Functional studies
experiments testing how genetic variants change cellular behavior have identified nearby SNPs in high linkage disequilibrium with rs1006737 that show allele-dependent regulatory activity, with the A risk allele associated with altered calcium channel expression patterns.

The mechanism appears to involve changes in intracellular calcium signaling that affect multiple neurobiological processes. In lymphoblastoid cells⁵⁵ lymphoblastoid cells
immune cells grown in culture that preserve genetic properties from individuals with bipolar disorder, A-allele carriers showed higher resting intracellular calcium levels. This calcium dysregulation ripples through neural circuits involved in emotion and cognition.

Brain imaging studies consistently show that A-allele carriers exhibit altered brain structure and function⁶⁶ altered brain structure and function
differences visible on MRI and fMRI scans. Specifically, the risk allele is associated with increased volume in emotion-processing regions (amygdala, anterior cingulate cortex), altered prefrontal-hippocampal connectivity⁷⁷ prefrontal-hippocampal connectivity
communication strength between brain regions critical for memory and executive function, and heightened amygdala reactivity during emotional tasks. Over time, A-allele carriers with bipolar disorder show accelerated age-related thinning of the prefrontal cortex.

The Evidence

The discovery of CACNA1C as a psychiatric risk gene came from large-scale GWAS⁸⁸ large-scale GWAS
genome-wide association study — screening the entire genome for disease associations published by Green and colleagues in 2009. The initial finding in 4,387 bipolar disorder cases reached borderline genome-wide significance (P=7×10⁻⁸). The critical validation came when the same variant showed cross-disorder effects: the A-allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) in independent samples.

Meta-analyses⁹⁹ Meta-analyses
statistical combination of results from multiple studies to increase power across European and Asian populations consistently confirm the association. A 2024 meta-analysis pooling 12,744 cases and 16,460 controls found significant associations under multiple genetic models, with an overall odds ratio of approximately 1.20 for bipolar disorder per A-allele. The effect size is modest but highly consistent across studies.

The cross-disorder nature of this variant is particularly striking. Analysis by the Psychiatric Genomics Consortium¹⁰¹⁰ Analysis by the Psychiatric Genomics Consortium
international collaboration analyzing genetic data from >100,000 individuals showed that CACNA1C SNPs confer shared risk across attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, schizophrenia, and major depressive disorder. This suggests the variant affects transdiagnostic symptom clusters — particularly emotional dysregulation and cognitive deficits — rather than neatly defined diagnostic categories.

Cognitive studies in healthy A-allele carriers reveal subtle but measurable differences¹¹¹¹ subtle but measurable differences
effects detectable even without psychiatric illness in brain function. Risk allele carriers show blunted reward responsiveness, reduced logical memory performance, and altered activation patterns during working memory tasks. These represent vulnerability markers — intermediate phenotypes¹²¹² intermediate phenotypes
heritable traits that sit between genes and clinical diagnosis that may predispose to mood episodes under stress.

Practical Actions

Unlike monogenic disorders, the CACNA1C risk allele doesn't mandate specific medical interventions in healthy individuals. The 1.2-fold increased risk is a nudge, not a verdict. However, understanding your calcium channel genetics can inform lifestyle strategies for mood stability and stress resilience.

Calcium and magnesium balance matters more when your calcium channels are genetically primed for dysregulation. L-type calcium channel function¹³¹³ L-type calcium channel function
electrical signaling through these channels depends on the electrochemical gradient is sensitive to extracellular calcium and magnesium concentrations. Magnesium acts as a natural calcium channel blocker at physiological concentrations, modulating the very channels encoded by CACNA1C.

Omega-3 fatty acids (EPA and DHA) improve mitochondrial membrane fluidity and have been shown to modulate calcium signaling¹⁴¹⁴ modulate calcium signaling
change how calcium flows through cellular systems in neural tissue. While not CACNA1C-specific, omega-3s are among the few dietary interventions with evidence for mood stabilization in psychiatric disorders.

Stress management takes on heightened importance. Gene-environment interaction studies¹⁵¹⁵ Gene-environment interaction studies
research examining how genes and environmental exposures combine to affect disease risk show that CACNA1C risk alleles interact with adverse life events to amplify depression risk. A-allele carriers exposed to threatening life events showed significantly higher rates of major depressive disorder than those with the same genotype but lower stress exposure. This suggests that reducing chronic stress exposure — through meditation, therapy, social support, or lifestyle modification — may have outsized benefits for risk allele carriers.

Exercise and meditation both promote neuroplasticity¹⁶¹⁶ neuroplasticity
the brain's capacity to reorganize neural pathways and improve stress resilience through multiple mechanisms, including enhancement of brain-derived neurotrophic factor (BDNF) and modulation of prefrontal-limbic connectivity — the same circuits affected by CACNA1C variants.

Notably, lithium and certain L-type calcium channel blockers¹⁷¹⁷ L-type calcium channel blockers
medications that reduce calcium influx through voltage-gated channels like nimodipine and isradipine show mood-stabilizing effects in bipolar disorder. While evidence linking CACNA1C genotype to lithium response is mixed and population-dependent, the mechanistic overlap is biologically plausible. If you're considering mood stabilizer treatment, sharing your CACNA1C status with your clinician may inform medication selection, though this is not yet standard clinical practice.

Interactions

The rs1006737 variant sits in a haplotype block¹⁸¹⁸ haplotype block
region of the genome where multiple variants are inherited together with at least 16 other CACNA1C SNPs in high linkage disequilibrium. Among these, rs4765905 shows the strongest evidence for direct regulatory function, consistently reducing gene expression in the risk haplotype. When evaluating CACNA1C-related risk, the rs1006737 genotype captures effects from this broader haplotype structure.

Cross-gene interactions are emerging. CACNA1C rs1006737 acts independently of the Bcl-2 rs956572 variant¹⁹¹⁹ Bcl-2 rs956572 variant
another genetic factor affecting intracellular calcium regulation, suggesting multiple genetic pathways converge on calcium homeostasis to influence psychiatric risk. Interactions with early life stress and trauma are well-documented, with risk alleles amplifying the psychiatric consequences of adverse childhood experiences.

The CACNA1C locus has also been implicated in Timothy syndrome²⁰²⁰ Timothy syndrome
rare disorder caused by gain-of-function mutations in CACNA1C leading to severe cardiac arrhythmias and autism when mutated in coding regions, though rs1006737 is a common regulatory variant with far milder effects. This reminds us that the same gene can harbor both rare high-impact mutations and common low-impact variants affecting related phenotypes.