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Bipolar Disord. 2014 Sep;16(6):583-91. doi: 10.1111/bdi.12203. Epub 2014 Apr 10.

Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data.

Author information

1
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.

Abstract

OBJECTIVES:

Genetic markers in the genes encoding ankyrin 3 (ANK3) and the α-calcium channel subunit (CACNA1C) are associated with bipolar disorder (BP). The associated variants in the CACNA1C gene are mainly within intron 3 of the gene. ANK3 BP-associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.

METHODS:

In order to screen both coding and non-coding regions to identify potential aetiological variants, we used whole-genome sequencing in 99 BP cases. Variants with markedly different allele frequencies in the BP samples and the 1,000 genomes project European data were genotyped in 1,510 BP cases and 1,095 controls.

RESULTS:

We found that the CACNA1C intron 3 variant, rs79398153, potentially affecting an ENCyclopedia of DNA Elements (ENCODE)-defined region, showed an association with BP (p = 0.015). We also found the ANK3 BP-associated variant rs139972937, responsible for an asparagine to serine change (p = 0.042). However, a previous study had not found support for an association between rs139972937 and BP. The variants at ANK3 and CACNA1C previously known to be associated with BP were not in linkage disequilibrium with either of the two variants that we identified and these are therefore independent of the previous haplotypes implicated by genome-wide association.

CONCLUSIONS:

Sequencing in additional BP samples is needed to find the molecular pathology that explains the previous association findings. If changes similar to those we have found can be shown to have an effect on the expression and function of ANK3 and CACNA1C, they might help to explain the so-called 'missing heritability' of BP.

KEYWORDS:

DNA sequencing; L-type calcium channel; allelic association study; ankyrin 3; bipolar disorder; genetic

PMID:
24716743
PMCID:
PMC4227602
DOI:
10.1111/bdi.12203
[Indexed for MEDLINE]
Free PMC Article

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