背景:几种遗传因素与散发性肌萎缩侧索硬化症(ALS)的发病机理及其表型有关,如疾病进展。这里,在这项研究中,我们旨在鉴定影响散发性ALS患者生存的基因.
方法:我们招募了1076名日本散发性ALS患者,其估算的基因型数据为7908526个变异。我们使用Cox比例风险回归分析,并对性别进行了加性模型调整,发病年龄和从基因分型数据计算的前两个主成分进行全基因组关联研究。我们进一步分析了来自ALS患者的诱导多能干细胞(iPSC-MN)的运动神经元中的信使RNA(mRNA)和表型表达。
结果:三个新基因座与散发性ALS-FGF1患者在5q31.3时的生存显着相关(rs11738209,HR=2.36(95%CI,1.77至3.15),p=4.85×10-9),THSD7A为7p21.3(rs2354952,1.38(95%CI,1.24至1.55),p=1.61×10-8)和LRP1在12q13.3(rs60565245,2.18(95%CI,1.66至2.86),p=2.35×10-8)。FGF1和THSD7A变体与iPSC-MNs中每个基因的mRNA表达降低以及从ALS患者获得的iPSC-MNs的体外存活率降低相关。当FGF1和THSD7A的表达被部分破坏时,iPSC-MN的体外存活降低。rs60565245与LRP1mRNA表达无关。
结论:我们确定了与散发性ALS患者生存相关的三个位点,降低FGF1和THSD7A的mRNA表达和患者iPSC-MN的活力。iPSC-MN模型反映了患者预后和基因型之间的关联,并且可以有助于治疗干预的目标筛选和验证。
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-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A 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 FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression.
We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A 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.