TY - JOUR
T1 - Functional characterization of schizophrenia-associated variation in CACNA1C
AU - Eckart, Nicole
AU - Song, Qifeng
AU - Yang, Rebecca
AU - Wang, Ruihua
AU - Zhu, Heng
AU - McCallion, Andrew S.
AU - Avramopoulos, Dimitrios
N1 - Funding Information:
This work was supported by NIH grants MH092515 and MH085018 to D.A. and NINDS grant R01 NS062972 to A.S.M. We thank the Harvard Brain Tissue Resource Center and the University of Maryland National Institute of Child Health and Human Development Brain Bank for providing tissue samples, and to Megan Szymanski Pierce who previously extracted DNA and RNA from STG tissue samples.
Publisher Copyright:
© 2016 Eckart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0157086
DO - 10.1371/journal.pone.0157086
M3 - Article
C2 - 27276213
AN - SCOPUS:84975318556
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 6
M1 - e0157086
ER -