Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data. (10th April 2014)

• Record Type: Journal Article
• Authors: Fiorentino, Alessia; O'Brien, Niamh Louise; Locke, Devin Paul; McQuillin, Andrew; Jarram, Alexandra; Anjorin, Adebayo; Kandaswamy, Radhika; Curtis, David; Blizard, Robert Alan; Gurling, Hugh Malcolm Douglas
• Is Part Of: Bipolar disorders. Volume 16:Number 6(2014)
• Page Start: 583
• Page End: 591
• Publication Date: 2014-04-10
• Subjects: Manic-depressive illness -- Periodicals; Depression, Mental -- Periodicals; 616.895
• DOI: 10.1111/bdi.12203
• Languages: English
• ISSNs: 1398-5647

Abstract

<abstract abstract-type="main" id="bdi12203-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bdi12203-sec-0001" sec-type="section"> <title>Objectives</title> <p>Genetic markers in the genes encoding ankyrin 3 (<italic>ANK3</italic>) and the α‐calcium channel subunit (<italic>CACNA1C</italic>) are associated with bipolar disorder (BP). The associated variants in the <italic>CACNA1C</italic> gene are mainly within intron 3 of the gene. <italic>ANK3 </italic>BP‐associated variants are in two distinct clusters at the ends of the gene, indicating disease allele heterogeneity.</p> </sec> <sec id="bdi12203-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bdi12203-sec-0003" sec-type="section"> <title>Results</title> <p>We found that the <italic>CACNA1C</italic> 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 <italic>ANK3 </italic>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 <italic>ANK3</italic> and <italic>CACNA1C</italic> 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.</p> </sec> <sec id="bdi12203-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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 <italic>ANK3</italic> and <italic>CACNA1C</italic>, they might help to explain the so‐called 'missing heritability' of BP.</p> </sec> </abstract>