Samochowiec Jerzy, Samochowiec Agnieszka, Puls Imke, Bienkowski Przemyslaw, Schott Björn H
Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland.
Neuropsychobiology. 2014;70(2):77-94. doi: 10.1159/000364826. Epub 2014 Oct 30.
BACKGROUND/AIMS: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated.
We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS).
Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity.
With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.
背景/目的：酒精依赖是一种常见的严重精神疾病，病因多因素。自人类基因组计划完成以来，随着高通量基因分型技术的日益普及，已确定了包括酒精依赖在内的多种与物质相关疾病的遗传风险因素，但并非所有结果都能被重复验证。
我们系统回顾了关于酒精依赖及酒精相关表型遗传风险因素的临床文献，包括基于候选基因的研究、连锁研究和全基因组关联研究（GWAS）。
无论采用何种方法，关于酒精依赖遗传风险因素最确凿的发现都涉及影响酒精代谢的基因变异。GWAS证实了4号染色体上酒精脱氢酶基因簇在酒精依赖遗传风险中的重要性，多个变异发挥着微小但累积的影响。对个体风险有强烈影响的一个单一变异是亚洲人群中常见的乙醛脱氢酶2（ALDH2）ALDH2*2变异。还发现了与KIAA0040等先前未鉴定的基因存在其他确凿关联，此类观察结果可能会导致发现迄今未知的信号通路。越来越多的证据也表明谷氨酸能、多巴胺能和5-羟色胺能神经递质信号在酒精依赖风险中起作用，但影响较小，且基因-环境相互作用进一步增加了复杂性。
除了像ALDH2*2这样的少数例外情况，单个基因变异对酒精相关疾病风险的贡献很小。然而，神经递质信号通路中风险变异的聚集可能有助于加深我们对潜在病理生理学的理解，从而有助于开发新的治疗策略。
