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Mol Psychiatry DOI:10.1038/mp.2015.165

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

Publication TypeJournal Article
Year of Publication2016
AuthorsSong, J, Bergen, SE, Di Florio, A, Karlsson, R, Charney, A, Ruderfer, DM, Stahl, EA, Chambert, KD, Moran, JL, Gordon-Smith, K, Forty, L, Green, EK, Jones, I, Jones, L, Scolnick, EM, Sklar, P, Smoller, JW, Lichtenstein, P, Hultman, C, Craddock, N, Landen, M, Smoller, JW, Perlis, RH, Lee, PHyoun, Castro, VM, Hoffnagle, AG, Sklar, P, Stahl, EA, Purcell, SM, Ruderfer, DM, Charney, AW, Roussos, P, Pato, CPato Miche, Medeiros, H, Sobel, J, Craddock, N, Jones, I, Forty, L, Di Florio, A, Green, E, Jones, L, Gordon-Smith, K, Landén, M, Hultman, C, Jureus, A, Bergen, S, McCarroll, S, Moran, J, Smoller, JW, Chambert, K, Belliveau, RA
Corporate AuthorsMembers of the International Cohort Collection for Bipolar Disorder (ICCBD)
JournalMol Psychiatry
Date Published2016 Sep
KeywordsAdult, Antimanic Agents, Biomarkers, Pharmacological, Bipolar Disorder, Carrier Proteins, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Lithium, Lithium Compounds, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Self Report, Sweden, United Kingdom

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.


Alternate JournalMol. Psychiatry
PubMed ID26503763
PubMed Central IDPMC4995544
Grant ListR01 MH106547 / MH / NIMH NIH HHS / United States
K99 MH101367 / MH / NIMH NIH HHS / United States
R01 MH106527 / MH / NIMH NIH HHS / United States
R01 MH106531 / MH / NIMH NIH HHS / United States
/ / Wellcome Trust / United Kingdom
MR/L010305/1 / / Medical Research Council / United Kingdom
R01 MH085542 / MH / NIMH NIH HHS / United States