Background: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence.
Aim: Identify risk genes and risk gene pathways for alcohol dependence.
Methods: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample.
Results: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the 'cellextracellular matrix interactions' pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the 'Na+/Cl- dependent neurotransmitter transporters' pathway and the 'other glycan degradation' pathway.
Conclusion: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.
背景: 信号通路中风险基因的构成可能可以解释酒精依赖风险基因协同的神经生物学作用。.
目的: 识别酒精依赖的风险基因和风险基因通路。.
方法: 我们采用基因富集 (gene-set-rich) 分析方法对酒精依赖进行了基于通路的全基因组关联分析 (GWAS)。在包括1409名欧裔美国人(European-American，EA)酒精依赖者和1518 名EA健康对照者的探索性样本人群中检测了近一百万个基因标志物。此外，将681名非裔美国人 (African-American, AA) 病例和508名AA健康受试者作为重测样本。.
结果: 我们发现了几个与酒精依赖显著相关的可重复的全基因组风险基因和风险通路。在多重比较Bonferroni校正后，“细胞- 细胞外基质相互作用”通路(EA样本中p<2.0E-4) 和该通路中PXN基因 (编码桩蛋白paxillin)(EA 样本中p=3.9E-7) 是最有可能的酒精依赖的危险因素。在EA样本 (0.015≤p≤0.035)和AA样本(0.025≤p≤0.050) 中还有两条富含酒精依赖相关基因的可重复的通路：“Na+/ Cl-依赖性神经递质转运体”通路和“其他聚糖降解”通路。.
结论: 一些基因和生物信号传导过程可能与酒精依赖的风险相关，本研究的发现为此提供了新的证据。.
中文全文: 本文全文中文版从2015年6月6日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215031可供免费阅览下载.
Keywords: PXN; alcohol dependence; cell-extracellular matrix interaction pathway; gene-based GWAS; pathway-based GWAS; paxillin.