Functional Characterization of Schizophrenia-Associated Variation in CACNA1C.
Nicole Eckart,Qifeng Song,Rebecca Yang,Ruihua Wang,Heng Zhu,Andrew S. McCallion,Dimitrios Avramopoulos +6 more
TLDR
The results elucidate the pathogenic relevance of one of the best-supported risk loci for schizophrenia and bipolar disorder and show interaction of the disease-associated region including the 16 SNPs with the CACNA1C promoter and other potential regulatory regions.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.read more
Citations
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Journal ArticleDOI
Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease
TL;DR: The molecular properties of calcium channels are reviewed, their multiple roles in synaptic plasticity are considered, and their potential involvement in this wide range of neuropsychiatric diseases is discussed.
Journal ArticleDOI
The Emerging Neurobiology of Bipolar Disorder
Paul Harrison,Paul Harrison,John R. Geddes,John R. Geddes,Elizabeth M. Tunbridge,Elizabeth M. Tunbridge +5 more
TL;DR: Two recent areas of progress are reviewed, the discovery of risk genes and their implications, with a focus on voltage-gated calcium channels as part of the disease process and as a drug target.
Journal ArticleDOI
CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis.
TL;DR: An overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning is presented.
Journal ArticleDOI
Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases.
Leina Lu,Xiaoxiao Liu,Wei-Kai Huang,Wei-Kai Huang,Paola Giusti-Rodríguez,Jian Cui,Shanshan Zhang,Wanying Xu,Zhexing Wen,Shufeng Ma,Jonathan D. Rosen,Zheng Xu,Cynthia F. Bartels,Riki Kawaguchi,Ming Hu,Peter C. Scacheri,Zhili Rong,Yun Li,Patrick F. Sullivan,Patrick F. Sullivan,Hongjun Song,Guo Li Ming,Yan Li,Yan Li,Fulai Jin +24 more
TL;DR: Interestingly, it is concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
Journal ArticleDOI
From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms
TL;DR: Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Cav1.2 and Cav.3.
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