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Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder

Sharp, SI; Lange, J; Kandaswamy, R; Daher, M; Anjorin, A; Bass, NJ; McQuillin, A; (2017) Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder. Psychiatric Genetics , 27 (3) pp. 81-88. 10.1097/YPG.0000000000000166. Green open access

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Abstract

Background: Bipolar affective disorder (BPD) is a severe mood disorder with a prevalence of ∼ 1.5% in the population. The pathogenesis of BPD is poorly understood; however, a strong heritable component has been identified. Previous genome-wide association studies have indicated a region on 6q25, coding for the SYNE1 gene, which increases disease susceptibility. SYNE1 encodes the synaptic nuclear envelope protein-1, nesprin-1. A brain-specific splice variant of SYNE1, CPG2 encoding candidate plasticity gene 2, has been identified. The intronic single-nucleotide polymorphism with the strongest genome-wide significant association in BPD, rs9371601, is present in both SYNE1 and CPG2. / Methods: We screened 937 BPD samples for genetic variation in SYNE1 exons 14–33, which covers the CPG2 region, using high-resolution melt analysis. In addition, we screened two regions of increased transcriptional activity, one of them proposed to be the CPG2 promoter region. / Results and Conclusion: We identified six nonsynonymous and six synonymous variants. We genotyped three rare nonsynonymous variants, rs374866393, rs148346599 and rs200629713, in a total of 1099 BPD samples and 1056 controls. Burden analysis of these rare variants did not show a significant association with BPD. However, nine patients are compound heterozygotes for variants in SYNE1/CPG2, suggesting that rare coding variants may contribute significantly towards the complex genetic architecture underlying BPD. Imputation analysis in our own wholegenome sequencing sample of 99 BPD individuals identified an additional eight risk variants in the CPG2 region of SYNE1.

Type: Article
Title: Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/YPG.0000000000000166
Publisher version: http://dx.doi.org/10.1097/YPG.0000000000000166
Language: English
Additional information: Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.
Keywords: bipolar affective disorder, CPG2, depressive disorder, genetic predisposition to disease, genetics, genome-wide association study, genotype, single-nucleotide polymorphism, SYNE1
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10049025
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