背景:肌萎缩侧索硬化症(ALS)患者在发病年龄(AAO)方面表现出很大的异质性,这与病程密切相关。然而,大多数基因研究都集中在ALS的风险上,而ALSAAO的遗传背景仍然未知。
方法:为了确定影响ALSAAO的遗传决定因素,我们使用Cox比例风险模型对中国人群中2,841例ALS患者(Ndiscovery=2,272,Nreplication=569)进行了全基因组关联分析.我们进一步使用公共顺式-eQTL数据集进行了共定位分析,和孟德尔随机化分析,以确定ALSAAO的危险因素。最后,进行了包括双荧光素酶报告基因测定和RT-qPCR的功能实验来探索目标变体的调节作用。
结果:ALSAAO的总遗传力为〜0.24。一个新基因座rs10128627(FRMD8)与〜3.15年的早期AAO显着相关(P=1.54E-08,β=0.31,SE=0.05)。该位点是NEAT1在多个脑组织和血液中的顺式eQTL。共定位分析检测到ALS的AAO与NEAT1表达之间的该基因座处的关联信号。此外,功能探索支持rs10128627变体与细胞模型和ALS患者中NEAT1表达上调相关.因果关系提示总胆固醇升高,低密度脂蛋白,嗜酸性粒细胞名义上与ALS的早期AAO相关,而单核细胞可能会延迟AAO。
结论:来自遗传的集体证据,生物信息学,和功能结果表明NEAT1是ALS疾病进展的关键参与者。这些发现提高了目前对ALS在AAO中的遗传作用的理解,为进一步研究其发病机制和延缓疾病发作的治疗方案提供了新的靶点。
Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown.
To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant.
The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO.
Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.