CACNA1C hypermethylation is associated with bipolar disorder.
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.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Starnawska
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Demontis
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
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Pen
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Hedemand
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Nielsen
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Staunstrup
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Grove
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Als
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
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Jarram
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
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O'Brien
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Research Department P, Aarhus University Hospital, Risskov, Denmark.
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Mors
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
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McQuillin
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Børglum
Department of Biomedicine, Aarhus University, Aarhus, Denmark.|The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.|Center for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
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Nyegaard
D001714:Bipolar Disorder / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012016:Reference Values; D012737:Sex Factors
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type