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 journalArticle

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.

Original languageEnglish (US)
Article numbere0157086
JournalPLoS One
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2016

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protein binding
Single Nucleotide Polymorphism
Schizophrenia
alleles
behavior disorders
calcium channels
Nucleic Acid Regulatory Sequences
Calcium Channels
Microarrays
linkage disequilibrium
Polymorphism
Introns
single nucleotide polymorphism
Chromatin
chromatin
Conformations
introns
quantitative trait loci
Assays
haplotypes

ASJC Scopus subject areas

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

Cite this

Functional characterization of schizophrenia-associated variation in CACNA1C. / Eckart, Nicole; Song, Qifeng; Yang, Rebecca; Wang, Ruihua; Zhu, Heng; McCallion, Andrew S; Avramopoulos, Dimitrios.

In: PLoS One, Vol. 11, No. 6, e0157086, 01.06.2016.

Research output: Contribution to journalArticle

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