• J Song, S E Bergen, A Di Florio, R Karlsson, A Charney, D M Ruderfer, E A Stahl, Members of the International Cohort Collection for Bipolar Disorder (ICCBD), K D Chambert, J L Moran, K Gordon-Smith, L Forty, E K Green, I Jones, L Jones, E M Scolnick, P Sklar, J W Smoller, P Lichtenstein, C Hultman, N Craddock, M Landén, Jordan W Smoller, Roy H Perlis, Phil Hyoun Lee, Victor M Castro, Alison G Hoffnagle, Pamela Sklar, Eli A Stahl, Shaun M Purcell, Douglas M Ruderfer, Alexander W Charney, Panos Roussos, Carlos Pato Michele Pato, Helen Medeiros, Janet Sobel, Nick Craddock, Ian Jones, Liz Forty, Florio Arianna Di AD, Elaine Green, Lisa Jones, Katherine Gordon-Smith, Mikael Landen, Christina Hultman, Anders Jureus, Sarah Bergen, Steven McCarroll, Jennifer Moran, Kimberly Chambert, and Richard A Belliveau.
• Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
• Mol. Psychiatry. 2016 Sep 1; 21 (9): 1290-7.

AbstractLithium 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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