期刊
BIPOLAR DISORDERS
卷 16, 期 6, 页码 583-591出版社
WILEY
DOI: 10.1111/bdi.12203
关键词
allelic association study; ankyrin 3; bipolar disorder; DNA sequencing; genetic; L-type calcium channel
资金
- Bipolar Organization
- Neuroscience Research Charitable Trust
- Central London NHS Blood Transfusion Service
- Stanley Medical Research Institute
- Cheshire and Wirral Partnership NHS Foundation Trust
- Cumbria Partnership NHS Foundation Trust
- Cambridgeshire and Peterborough NHS Foundation Trust
- Suffolk Mental Health Partnership NHS Trust
- South Essex Partnership University NHS Foundation Trust
- West London Mental Health NHS Trust
- Camden and Islington NHS Foundation Trust
- East London NHS Foundation Trust
- North East London Mental Health NHS Trust
- Hertfordshire Partnership NHS Foundation Trust
- Berkshire Healthcare NHS Foundation Trust
- North Essex Partnership NHS Foundation Trust
- Oxfordshire and Buckinghamshire Mental Health NHS Foundation Trust
- South London and Maudsley NHS Foundation Trust
- Oxleas NHS Foundation Trust
- Surrey and Borders Partnership NHS Foundation Trust
- Kent and Medway NHS
- Social Care Partnership Trust
- South West London and St George's Mental Health NHS Trust
- Sussex Partnership Trust
- Cornwall Partnership NHS Trust
- Somerset Partnership NHS Foundation Trust
- Salisbury NHS Foundation Trust
- Central and North West London NHS Foundation Trust
- National Institute for Health Research Mental Health Research Network
- NIHR-supported Primary Care Research Network
- UK Medical Research Council [G9623693N, G0500791, G0701007, G1000708]
- UCL IMPACT award and Equilibrium
- Bipolar Foundation
- UK government Overseas Research Student award
- Stanley Foundation
- Stanley Psychiatric Research Center at the Broad Institute, Boston, MA, USA
- Medical Research Council [G0500791, G1000708, G0701007] Funding Source: researchfish
- MRC [G1000708, G0701007, G0500791] Funding Source: UKRI
Objectives Genetic markers in the genes encoding ankyrin 3 (ANK3) and the -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.
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