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Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Song, J., Bergen, S.E., Di Florio, A., Karlsson, R., Charney, A., Ruderfer, D.M., Stahl, E.A., Members of, I.C.C.B.D., Chambert, K.D., Moran, J.L., Gordon-Smith, Katherine, Forty, L., Green, E.K., Jones, I., Jones, Lisa, Scolnick, E.M., Sklar, P., Smoller, J.W., Lichtenstein, P., Hultman, C., Craddock, N. and Landén, M. (2016) Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder. Molecular Psychiatry, 21. pp. 1290-1297. ISSN Print: 1359-4184 Online: 1476-5578

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Abstract

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

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Uncontrolled Keywords: genome-wide association study, bipolar disorder, lithium responsiveness, SESTD1
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: Academic Departments > Institute of Health and Society
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Copyright Info: Open Access article
Depositing User: Lisa Jones
Date Deposited: 05 Nov 2015 12:06
Last Modified: 04 Nov 2016 08:55
URI: https://eprints.worc.ac.uk/id/eprint/4030

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