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

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.

SUBMITTER: Song J

PROVIDER: S-EPMC4995544 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Song J J Bergen S E SE Di Florio A A Karlsson R R Charney A A Ruderfer D M DM Stahl E A EA Chambert K D KD Moran J L JL Gordon-Smith K K Forty L L Green E K EK Jones I I Jones L L Scolnick E M EM Sklar P P Smoller J W JW Lichtenstein P P Hultman C C Craddock N N Landén M M Smoller Jordan W JW Perlis Roy H RH Lee Phil Hyoun PH Castro Victor M VM Hoffnagle Alison G AG Sklar Pamela P Stahl Eli A EA Purcell Shaun M SM Ruderfer Douglas M DM Charney Alexander W AW Roussos Panos P Michele Pato Carlos Pato CP Medeiros Helen H Sobel Janet J Craddock Nick N Jones Ian I Forty Liz L Florio Arianna Di AD Green Elaine E Jones Lisa L Gordon-Smith Katherine K Landen Mikael M Hultman Christina C Jureus Anders A Bergen Sarah S McCarroll Steven S Moran Jennifer J Smoller Jordan W JW Chambert Kimberly K Belliveau Richard A RA

Molecular psychiatry 20151027 9

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. Patie ...[more]

PMID: 26503763

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Project description:BackgroundLithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.MethodsHere, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).InterpretationThe response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Dataset Information

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

Publications

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

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