Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.
Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.
复制标题
全基因组关联研究将 SESTD1 确定为锂反应性双相情感障碍的新风险基因。
DOI：
10.1038/mp.2015.165
复制
发表时间：
2016
影响因子：
11
通讯作者：
Scol
中科院分区：
文献类型：
--
作者：
Song,J;Bergen,SE;DiFlorio,A;Karlsson,R;Charney,A;Ruderfer,DM;Stahl,EA;MembersoftheInternationalCohortCollectionforBipolarDisorder(ICCBD);Chambert,KD;Moran,JL;Gordon-Smith,K;Forty,L;Green,EK;Jones,I;Jones,L;Scol
锂是双相情感障碍 (BD) 的主要预防性治疗方法，但治疗效果因人而异。对锂治疗反应良好的患者可能代表这种遗传和表型多样化疾病的相对同质亚型。在这里，我们进行了全基因组关联研究 (GWAS)，以确定 (i) 影响锂反应的特定遗传变异和 (ii) 与锂反应 BD 风险相关的遗传变异。双相情感障碍患者和对照组是从瑞典和英国招募的。对 2698 名具有主观定义（自我报告）锂反应的患者和 1176 名具有客观定义（临床记录）锂反应的患者进行了 GWAS。接下来，我们进行了 GWAS，将锂反应者与健康对照者（1639 名主观反应者和 8899 名对照者；323 名客观反应者和 6684 名对照者）进行了比较。对瑞典和英国结果的荟萃分析显示，双相情感障碍受试者的锂反应与锂反应没有显着关联。然而，当将锂反应患者与对照组进行比较时，两个估算标记获得了全基因组显着关联，其中一个在验证性基因分型中得到了验证（rs116323614，P = 2.74×10−8）。它是染色体 2q31 上的内含子单核苷酸多态性 (SNP)。 2 位于基因 SEC14 和血影蛋白结构域 1 (SESTD1) 中，后者编码参与磷脂调节的蛋白质。磷脂被强烈认为是锂治疗的目标。此外，我们使用锂反应的两种定义估计了由常见变异（“SNP 遗传力”）解释的锂反应 BD 的方差比例为 0.25 和 0.29。我们的结果揭示了 SESTD1 中的一个遗传变异与锂反应性 BD 风险相关，这表明通过关注这种 BD 亚型可以进一步加深对 BD 病因学的理解。
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.