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

• Published in: Molecular psychiatry Vol. 21; no. 9; pp. 1290 - 1297
• Main Authors: Song, J, Bergen, S E, Di Florio, A, Karlsson, R, Charney, A, Ruderfer, D M, Stahl, E A, Chambert, K D, Moran, J L, Gordon-Smith, K, Forty, L, Green, E K, Jones, I, Jones, L, Scolnick, E M, Sklar, P, Smoller, J W, Lichtenstein, P, Hultman, C, Craddock, N, 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, Charney, Alexander W, Roussos, Panos, Michele Pato, Carlos Pato, Medeiros, Helen, Sobel, Janet, Craddock, Nick, Jones, Ian, Forty, Liz, Florio, Arianna Di, Green, Elaine, Jones, Lisa, Gordon-Smith, Katherine, Landen, Mikael, Hultman, Christina, Jureus, Anders, Bergen, Sarah, McCarroll, Steven, Moran, Jennifer, Chambert, Kimberly, Belliveau, Richard A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2016; Nature Publishing Group
• Subjects: 38/43; 631/208; 692/699/476/1333; Adult; Antimanic Agents - therapeutic use; Behavioral Sciences; Biochemistry & Molecular Biology; Biological Psychology; Biomarkers, Pharmacological - blood; Bipolar disorder; Bipolar Disorder - genetics; Bipolar Disorder - metabolism; brain; Care and treatment; Carrier Proteins - genetics; Carrier Proteins - metabolism; Development and progression; Female; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic Variation; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Genotype; Health aspects; Humans; japanese patients; Kinases; Lithium; Lithium - metabolism; Lithium - therapeutic use; Lithium Compounds - therapeutic use; maintenance treatment; Male; mechanism; Medicine; Medicine & Public Health; Methods; Middle Aged; Neurosciences; Neurosciences & Neurology; neurotrophic factor gene; Original; original-article; Pathophysiology; Pharmacotherapy; Physiology; polymorphism; Polymorphism, Single Nucleotide - genetics; prophylactic; Proteins; Psychiatry; Psykiatri; receptor potential channels; Risk Factors; schizophrenia; Self Report; Sweden; trpc5 channels; United Kingdom; New York; Sweden; United Kingdom > UK; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.165

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.