Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.
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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. |
Year of Publication | 2016
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Journal | Mol Psychiatry
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Volume | 21
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Issue | 9
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Pages | 1290-7
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Date Published | 2016 Sep
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ISSN | 1476-5578
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DOI | 10.1038/mp.2015.165
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PubMed ID | 26503763
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PubMed Central ID | PMC4995544
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Grant list | R01 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
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