Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.

Abstract

Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. Three novel loci were significantly associated with the survival of patients with sporadic ALS-<i>FGF1</i> at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10^-9), <i>THSD7A</i> at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10^-8) and <i>LRP1</i> at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10^-8). <i>FGF1</i> and <i>THSD7A</i> variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of <i>FGF1</i> and <i>THSD7A</i> was partially disrupted. The rs60565245 was not associated with <i>LRP1</i> mRNA expression. We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of <i>FGF1</i> and <i>THSD7A</i> and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.