Functional Characterization of Schizophrenia-Associated Variation in CACNA1C

Abstract

Calcium channel subunits, including CACNA1C, have been associated with multiple psychiatric disorders. Specifically, genome wide association studies (GWAS) have repeatedly identified the single nucleotide polymorphism (SNP) rs1006737 in intron 3 of CACNA1C to be strongly associated with schizophrenia and bipolar disorder. Here, we show that rs1006737 marks a quantitative trait locus for CACNA1C transcript levels. We test 16 SNPs in high linkage disequilibrium with rs1007637 and find one, rs4765905, consistently showing allele-dependent regulatory function in reporter assays. We find allele-specific protein binding for 13 SNPs including rs4765905. Using protein microarrays, we identify several proteins binding ≥3 SNPs, but not control sequences, suggesting possible functional interactions and combinatorial haplotype effects. Finally, using circular chromatin conformation capture, we show interaction of the disease-associated region including the 16 SNPs with the CACNA1C promoter and other potential regulatory regions. Our results elucidate the pathogenic relevance of one of the best-supported risk loci for schizophrenia and bipolar disorder.

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α

“…To date all disease-associated CACNA1C SNPs are intronic 1 with both an increase 57,58 and decrease 26,27,58,59 in CACNA1C expression and function reported in human samples. Irrespective, given that Ca v 1.2 channels play a crucial role in various neuronal functions, we hypothesize that higher or lower Ca 2+ influx in neurons can alter neuronal and brain function and impact behavior in patients.…”

Recent Advances in the Genetics of Schizophrenia

“…Beyond the group enrichments and network analyses described above, many studies have begun to link variants to specific genes as eQTLs and experimentally follow them up to understand the biological consequences of these variants. Examples include signals near ZNF804A [103, 104], TCF4 [105], and CACNA1C [106, 107]. The most detailed and well publicized such study has been that of Sekar et al [108] in the HLA region.…”

[P3–102]: Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease

“…Although the genetic mechanism underlying these associations remains an area of active inquiry, 87 convergent data suggests that schizophrenia is associated with reduced voltage-dependent calcium channel function. [88][89][90] How reductions in voltage-dependent calcium channel function may further increase AD+P risk is not known, however, impairments of intracellular Ca 2+ homeostasis are present in AD, and can contribute to synaptic dysfunction and cognitive impairments.…”

“…77 Sherlock indicates additional results of analyses of the CommonMind Consortium data set conducted using a Bayesian approach to prioritize consistency between the disease and eQTL associations in each of the schizophrenia GWAS loci. 87 This approach is motivated by recognition that the presence of an eQTL is not sufficient to indicate disease causality and that many SNPs within a locus are highly correlated, thus examination of the joint association of SNP and eQTL is more likely to identify genes contributing to disease risk. Genes identified by Sherlock with a corrected p < 0.05 are shown.…”