In the authors' opinion, both of these authors contributed equally to the work and should be considered joint first authors.
Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data
Article first published online: 10 APR 2014
© 2014 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
How to Cite
Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. Bipolar Disord 2014: 00: 000–000. © 2014 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd., , , , , , , , , .
- Article first published online: 10 APR 2014
- Manuscript Accepted: 27 DEC 2013
- Manuscript Received: 19 SEP 2013
- UK Medical Research Council. Grant Numbers: G9623693N, G0500791, G0701007, G1000708
- UCL IMPACT
- Bipolar Foundation
- UK government
- Stanley Foundation
- Stanley Psychiatric Research Center
- Broad Institute
- allelic association study;
- ankyrin 3;
- bipolar disorder;
- DNA sequencing;
- L-type calcium channel
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.
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.
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.
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.