Abstract
The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10−7 for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10−7) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation.
Highlights
Bipolar disorder (BD) is a common complex mental disorder characterized by episodes of mania, hypomania and depression.The disorder affects ~ 1% of the population and the genetic risk component is high with heritability estimates reaching 89%.1,2CACNA1C is one of the most consistently associated BD genes
The University College London (UCL) cases comprised Caucasian individuals who were ascertained and received clinical diagnoses of BD according to UK National Health Service (NHS) psychiatrists at interview using the categories of the International Classification of Disease version 10 (ICD10), as described in a previous BD genome-wide association study (GWAS).[5]
We profiled the DNA methylation landscape of five CpG island (CGI) in CACNA1C in blood-derived DNA and found CGI 3 to be significantly hypermethylated in BD subjects compared with controls
Summary
Bipolar disorder (BD) is a common complex mental disorder characterized by episodes of mania, hypomania and depression.The disorder affects ~ 1% of the population and the genetic risk component is high with heritability estimates reaching 89%.1,2CACNA1C is one of the most consistently associated BD genes. Bipolar disorder (BD) is a common complex mental disorder characterized by episodes of mania, hypomania and depression. The disorder affects ~ 1% of the population and the genetic risk component is high with heritability estimates reaching 89%.1,2. CACNA1C is one of the most consistently associated BD genes. CACNA1C, encodes the pore-forming α1C subunit of the L-type voltage-gated calcium channel referred to as Cav1.2 α1C subunit. In the central nervous system, Cav1.2 channels are predominantly located in the postsynaptic dendritic processes and somata. The Cav1.2 channels allow postsynaptic influx of calcium ions coupled with activation of neuronal transcription factors involved in dendritic development, neuronal survival, synaptic plasticity, as well as memory formation and learning.[3,4]
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