全基因组分析鉴定 NEAT1 为肌萎缩侧索硬化发病年龄的遗传修饰因子。

Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis.

机构信息

Department of Neurology, Laboratory of Neurodegenerative Disorders, West China Hospital, National Clinical Research Center for Geriatric, Sichuan University, Chengdu, China.

出版信息

Mol Neurodegener. 2023 Oct 23;18(1):77. doi: 10.1186/s13024-023-00669-6.

DOI:10.1186/s13024-023-00669-6

PMID:37872557

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10594666/

Abstract

BACKGROUND

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.

METHODS

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 (N = 2,272, N = 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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

肌萎缩侧索硬化症（ALS）患者的发病年龄（AAO）存在很大的异质性，这与疾病的病程密切相关。然而，大多数遗传研究都集中在 ALS 的风险上，而 ALS 的 AAO 的遗传背景仍不清楚。

方法

为了确定影响 ALS 发病年龄的遗传决定因素，我们在中国人群中对 2841 名 ALS 患者（N=2272，N=569）使用 Cox 比例风险模型进行了全基因组关联分析。我们进一步使用公共顺式-eQTL 数据集进行共定位分析，并进行孟德尔随机化分析以确定 ALS 发病年龄的危险因素。最后，通过双荧光素酶报告基因检测和 RT-qPCR 进行了功能实验，以探讨目标变异的调控作用。

结果

ALS 发病年龄的总遗传率约为 0.24。一个新的位点 rs10128627（FRMD8）与 AAO 提前约 3.15 年显著相关（P=1.54E-08，β=0.31，SE=0.05）。该位点是多个脑组织和血液中 NEAT1 的顺式-eQTL。共定位分析在该位点检测到 ALS 的发病年龄与 NEAT1 的表达之间存在关联信号。此外，功能探索支持变异 rs10128627 与细胞模型和 ALS 患者中 NEAT1 的表达上调有关。因果推断表明，总胆固醇、低密度脂蛋白和嗜酸性粒细胞与 ALS 的 AAO 提前发生有显著关联，而单核细胞可能会延迟 AAO 的发生。