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CACNA1C hypermethylation is associated with bipolar disorder
A Starnawska1,2,3, D Demontis1,2,3, A Pen1,4
1Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Translational Psychiatry
|June 9, 2016
Summary
DNA methylation of the CACNA1C gene is altered in bipolar disorder (BD). This study found significant hypermethylation in BD cases, suggesting a role for epigenetic changes in BD pathogenesis and CACNA1C gene regulation.
Area of Science:
- Neuroscience
- Genetics
- Epigenetics
Background:
- CACNA1C gene, encoding a calcium channel subunit, is a key susceptibility gene for bipolar disorder (BD).
- Genome-wide association studies link non-coding single-nucleotide polymorphisms (SNPs) in CACNA1C intron 3 to BD and schizophrenia risk.
- Altered CACNA1C gene expression is a proposed mechanism for BD risk, but its DNA methylation status in BD remains uninvestigated.
Purpose of the Study:
- To investigate potential alterations in CACNA1C DNA methylation in individuals with bipolar disorder.
- To explore the relationship between CACNA1C methylation, genetic variants, and BD.
Main Methods:
- DNA methylation analysis of five CpG islands (CGIs) across the CACNA1C gene in blood samples from BD patients and healthy controls.
- Focused analysis on CGI 3 in intron 3 using a larger cohort (n=582 BD, n=319 controls).
- Investigated methylation quantitative trait loci (mQTLs) and associations with clinical characteristics.
Main Results:
- One CGI (CGI 3) in intron 3 exhibited intermediate methylation levels.
- Significant hypermethylation of five out of six CpG sites in CGI 3 was observed in BD cases compared to controls (lowest P=1.16 × 10(-7)).
- The SNP rs2238056 in intron 3 was identified as the strongest mQTL for CpG35 (P=2.6 × 10(-7)), influencing methylation levels.
- Increased CACNA1C methylation was found in females, with no significant difference between Bipolar I and II subtypes.
Conclusions:
- CACNA1C DNA methylation is significantly associated with bipolar disorder.
- Epigenetic dysregulation, specifically altered DNA methylation patterns in CACNA1C, likely contributes to BD pathogenesis.
- The identified risk-associated non-coding variants may exert their effects through modulation of CACNA1C DNA methylation.
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