Gene-based and pathway-based genome-wide association study of alcohol dependence

• Published in: Shanghai Jingshen Yixue Vol. 27; no. 2; pp. 111 - 118
• Main Authors: Zuo, Lingjun, Zhang, Clarence K, Sayward, Frederick G, Cheung, Kei-Hoi, Wang, Kesheng, Krystal, John H, Zhao, Hongyu, Luo, Xingguang
• Format: Journal Article
• Language: English
• Published: China Shanghai Municipal Bureau of Publishing 25.04.2015
• Subjects: Original; 信号通路; 全基因组; 关联; 基础; 相互作用; 神经生物学; 细胞外基质; 酒精; gene-based GWAS; paxillin; alcohol dependence; cell-extracellular matrix interaction pathway; PXN; pathway-based GWAS
• ISSN: 1002-0829
• DOI: 10.11919/j.issn.1002-0829.215031

Background： The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aims： 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 discovew 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 ＇cell- extracellular 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. Conclusions： These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.