Functional characterization of schizophrenia-associated variation in CACNA1C

Nicole Eckart, Qifeng Song, Rebecca Yang, Ruihua Wang, Heng Zhu, Andrew S. McCallion, Dimitrios Avramopoulos

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere0157086
JournalPloS one
Issue number6
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


Dive into the research topics of 'Functional characterization of schizophrenia-associated variation in CACNA1C'. Together they form a unique fingerprint.

Cite this