肌萎缩侧索硬化症（amyotrophic lateral sclerosis，ALS）是一种以运动神经元进行性死亡为特征的神
经系统退行性疾病，临床治疗手段匮乏且预后极差。随着近年来对ALS致病机制的深入探究，遗传因素在
其病理过程中的核心作用日益凸显。既往研究多聚焦于家族性ALS中高外显率的经典致病基因，遗传因
素在散发性ALS中的作用尚未阐明。风险基因通常是基因组中具有微小效应的遗传变异，通过多基因协
同、表观遗传调控及基因-环境互作以微小累积效应调控疾病的易感性。近年来，高通量测序与多组学技术的
联合应用揭示了数十个ALS新风险基因，明确新风险基因的可能作用机制将为解析ALS遗传因素提供新的
分子生物学证据。本综述系统总结了近五年新发现的ALS风险基因的分子调控机制及其在核心病理通路
中的潜在作用，强调其作为精准治疗靶点的转化潜力。通过整合多组学数据与基因编辑技术，推动风险基
因研究成果向临床转化，有望突破ALS治疗困境，为基于遗传学机制的ALS个体化诊疗提供理论依据。
Amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive mo
tor neuron loss, currently lacks effective clinical treatments and carries an extremely poor prognosis. Recent ad
vances in understanding ALS pathogenesis have increasingly highlighted the central role of genetic factors—par
ticularly as most prior studies focused on high-penetrance classic genes in familial cases, leaving sporadic ALS
genetic architecture largely unexplained. Risk genes typically represent small-effect genetic variants across the
genome that collectively influence disease susceptibility through polygenic interactions, epigenetic modifica
tions, and gene-environment interplay. Breakthroughs from high-throughput sequencing coupled with
multi-omics technologies have identified dozens of novel ALS risk genes in recent years. Elucidating their func
tional mechanisms could provide crucial molecular evidence for decoding ALS heritability patterns. This review
systematically summarizes molecular regulatory mechanisms of newly discovered ALS risk genes over the past
five years, evaluates their potential roles in core pathogenic pathways, and emphasizes their translational poten
tial as precision therapy targets. By integrating multi-omics datasets with gene editing tools, we aim to acceler
ate clinical translation of these findings—potentially transforming ALS management through personalized medi
cine grounded in genetic insights.
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