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

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_discovery = 2,272, N_replication = 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.

Keywords: Age at onset; Amyotrophic Lateral Sclerosis; GWAS; Genetic modifiers; NEAT1.