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Analysis of ANK3 and CACNA1C variants identified in bipolar disorder whole genome sequence data
Author(s) -
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
Publication year - 2014
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/bdi.12203
Subject(s) - genetics , biology , genetic association , gene , genome wide association study , genome , linkage disequilibrium , allele , haplotype , single nucleotide polymorphism , genotype
Objectives Genetic markers in the genes encoding ankyrin 3 ( ANK 3 ) and the α‐calcium channel subunit ( CACNA 1C ) are associated with bipolar disorder ( BP ). The associated variants in the CACNA 1C gene are mainly within intron 3 of the gene. ANK 3 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 CACNA 1C 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 ANK 3 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 ANK 3 and CACNA 1C 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 ANK 3 and CACNA 1C , they might help to explain the so‐called ‘missing heritability’ of BP .