Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.
Genetic variants associated with response to lithium treatment in bipolar disorder: a genome-wide association study.
复制标题
DOI：
10.1016/s0140-6736(16)00143-4
复制
发表时间：
2016-03-12
期刊：
影响因子：
--
通讯作者：
Schulze TG
中科院分区：
文献类型：
--
作者：
Hou L;Heilbronner U;Degenhardt F;Adli M;Akiyama K;Akula N;Ardau R;Arias B;Backlund L;Banzato CEM;Benabarre A;Bengesser S;Bhattacharjee AK;Biernacka JM;Birner A;Brichant-Petitjean C;Bui ET;Cervantes P;Chen GB;Chen HC;Chillotti C;Cichon S;Clark SR;Colom F;Cousins DA;Cruceanu C;Czerski PM;Dantas CR;Dayer A;Étain B;Falkai P;Forstner AJ;Frisén L;Fullerton JM;Gard S;Garnham JS;Goes FS;Grof P;Gruber O;Hashimoto R;Hauser J;Herms S;Hoffmann P;Hofmann A;Jamain S;Jiménez E;Kahn JP;Kassem L;Kittel-Schneider S;Kliwicki S;König B;Kusumi I;Lackner N;Laje G;Landén M;Lavebratt C;Leboyer M;Leckband SG;Jaramillo CAL;MacQueen G;Manchia M;Martinsson L;Mattheisen M;McCarthy MJ;McElroy SL;Mitjans M;Mondimore FM;Monteleone P;Nievergelt CM;Nöthen MM;Ösby U;Ozaki N;Perlis RH;Pfennig A;Reich-Erkelenz D;Rouleau GA;Schofield PR;Schubert KO;Schweizer BW;Seemüller F;Severino G;Shekhtman T;Shilling PD;Shimoda K;Simhandl C;Slaney CM;Smoller JW;Squassina A;Stamm T;Stopkova P;Tighe SK;Tortorella A;Turecki G;Volkert J;Witt S;Wright A;Young LT;Zandi PP;Potash JB;DePaulo JR;Bauer M;Reininghaus EZ;Novák T;Aubry JM;Maj M;Baune BT;Mitchell PB;Vieta E;Frye MA;Rybakowski JK;Kuo PH;Kato T;Grigoroiu-Serbanescu M;Reif A;Del Zompo M;Bellivier F;Schalling M;Wray NR;Kelsoe JR;Alda M;Rietschel M;McMahon FJ;Schulze TG
锂仍然是双相情感障碍的一线治疗，但个体反应是可变的。以前的研究表明，锂反应是一种遗传性状。然而，没有遗传标记已被重复确定。在这里，我们报告了一项锂反应的全基因组关联研究的结果，该研究由国际锂遗传学联盟（ConLiGen）的22个参与站点收集了2，563名患者;这是迄今为止最大的尝试。对来自600多万个常见单核苷酸多态性（SNP）的数据进行了测试，以确定其与已知可靠性的锂反应的分类和连续评级的相关性。21号染色体上的4个连锁SNP的单个位点符合与锂反应相关的全基因组显著性标准（rs79663003：p=1·37×10−8; rs78015114：p=1·31×10−8; rs74795342：p=3·31×10−9; rs75222709：p=3·50×10−9）。在一项对73名接受锂单药治疗长达两年的患者进行的独立前瞻性研究中，反应相关等位基因携带者的复发率显著低于替代等位基因携带者（p= 0.03，风险比= 3.8）。应答相关区包含两个编码长链非编码RNA（lncRNA）的基因，AL157359.3和AL157359.4。LncRNA作为基因表达的重要调节因子越来越受到重视，特别是在CNS中。需要进一步的研究来建立这些发现的生物学背景及其潜在的临床实用性。锂反应的确认生物标志物将构成双相情感障碍临床管理的重要一步。
Lithium remains 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 have been reproducibly identified. Here we report the results of a genome-wide association study of lithium response in 2,563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen); the largest attempted so far. Data from over 6 million common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response of known reliability. A 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; rs75222709: p=3·50×10−9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to two years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03, hazard ratio = 3·8). The response-associated region contains two genes coding 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. Further studies are needed to establish the biological context of these findings and their potential clinical utility. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder.