XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans
XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans
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DOI：
10.1038/npp.2014.178
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发表时间：
2015-01-01
影响因子：
7.6
通讯作者：
Rietschel, Marcella
中科院分区：
文献类型：
--
作者：
Juraeva, Dilafruz;Treutlein, Jens;Rietschel, Marcella
在酒精依赖（alcohol dependence，AD）的病因学中，遗传因素与环境因素同样重要.虽然全基因组关联研究（GWAS）能够系统地搜索迄今为止与AD病因学无关的基因座，但由于多次检测的校正，许多真正的发现可能会被遗漏。本研究的目的是通过寻找生物系统水平的差异来规避这一限制，然后在人类和动物中跟踪这些发现。对来自1333例病例和2168例对照的GWAS数据进行基于基因集的分析，确定了19个显著相关的基因集，其中5个可以在独立样本中重复。在这些基因集中发现了新的和以前鉴定的易感基因。最常见的基因，即在19个基因组中的6个，是中国仓鼠细胞5（XRCC5）中的X射线修复互补缺陷修复。先前的人类和动物研究表明XRCC5与酒精敏感性有关。这种表型与AD的发展呈负相关，可能是因为需要更多的酒精才能达到预期的效果。在本研究中，XRCC5在AD中的功能作用在动物和人类中得到了进一步验证。由于RNAi沉默，Ku80（哺乳动物XRCC5的同源物）功能降低的果蝇突变体对乙醇的敏感性降低。在实验室中自由静脉注射乙醇的人中，最大血液酒精浓度以等位基因剂量依赖性方式受到XRCC5基因变异的影响。总之，我们的融合方法确定了新的候选人，并产生了XRCC5参与酒精依赖的独立证据。
Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.