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

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Song, J. ; Bergen, S.E. ; Di Florio, Arianna ; Karlsson, R. ; Charney, A. ; Ruderfer, D. M. ; Stahl, E. A. ; Chambert, K. D. ; Moran, J. L. ; Gordon-Smith, K. ; Forty, Elizabeth ; Green, E. K. ; Jones, Ian Richard ; Jones, L ; Scolnick, E. M. ; Sklar, P. ; Smoller, J. W. ; Lichtenstein, P. ; Hultman, C. ; Craddock, Nicholas John ; Landén, M. ; Smoller, Jordan W. ; Perlis, Roy H. ; Lee, Phil Hyoun ; Castro, Victor M. ; Hoffnagle, Alison G. ; Sklar, Pamela ; Stahl, Eli A. ; Purcell, Shaun M. ; Ruderfer, Douglas M. ... view all 47 authors (2016)
  • Publisher: Nature Publishing Group
  • Journal: Molecular Psychiatry (issn: 1359-4184, vol: 21, pp: 1,290-1,297)
  • Related identifiers: doi: 10.1038/mp.2015.165, pmc: PMC4995544
  • Subject: Original Article | RC0321

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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