肌萎缩侧索硬化症(ALS)的发病年龄是高度可变的(例如,在C9orf72的G4C2扩展运营商工作了27-74年)。它可能通过CpG位点的DNA甲基化(DNAm)的调节而受到环境和遗传因素的影响。因此,我们结合表观遗传学和遗传学方法来检验以下假设:CpG位点(CpG-SNPs)的一些常见单核苷酸多态性(SNPs)可以改变ALS发病年龄.我们的全基因组DNAm分析显示,在249名ALS患者中,有3个CpG-SNPs的DNAm水平与发病年龄显著相关(q<0.05)。接下来,遗传分析验证了rs4970944与发现(n=469;P=0.025)和复制(n=4160;P=0.007)ALS队列中发病年龄的相关性.综合队列的荟萃分析显示,AA携带者的中位发病时间比GG携带者晚两年(n=4629;P=0.0012)。观察到与标记SNP相似的关联,暗示1q21.3基因座处的16Kb区域作为ALS发病年龄的修饰因子。值得注意的是,rs4970944基因型也与C9orf72携带者的发病年龄相关(n=333;P=0.025),表明每个A等位基因延迟发病1.6年。基因型组织表达数据的分析显示,保护性A等位基因与小脑中CTSS的表达降低有关(P=0.00018),它是分布式神经回路中的关键大脑区域,为运动控制提供服务。CTSS编码在抗原呈递中起关键作用的组织蛋白酶S蛋白。总之,我们确定了一个由rs4970944标记的16Kb基因座作为ALS发病年龄的修饰因子。我们的发现支持抗原呈递过程在调节ALS发病年龄中的作用,并提示潜在的药物靶标(例如,CTSS)。鼓励未来的复制研究,以验证rs4970944标记的基因座与独立ALS队列中发病年龄之间的联系,包括不同的民族。
Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a
modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a
modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.