Combined epigenetic/genetic study identified an ALS age of onset modifier

Ming Zhang,Mahdi Montazer Haghighi,Ekaterina Rogaeva,Danielle Moreno,Ruth Chia,Sara Saez-Atienzar,Lorne Zinman,Bryan J Traynor,Zhengrui Xi,Christine Sato

doi:10.1186/s40478-021-01183-w

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of upper and lower motor neurons in the brain and spinal cord, leading to paralysis [6]
Among the 4300 common CpG-single nucleotide polymorphisms (SNPs) with a multimodal distribution, the DNA methylation (DNAm) levels at 10 CpG-SNPs were associated with age of onset at a false discovery rate < 0.05, three of which remained significant after adjustment for sex, site of onset, DNAm-age acceleration and the top 5 principal components (PCs) (Fig. 2a, b, Additional file 1: Table S1, Fig. S1)
We conducted a genetic analysis of candidate variants detected during the DNAm study in an expanded Canadian ALS cohort (n = 469; Table 1)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of upper and lower motor neurons in the brain and spinal cord, leading to paralysis [6]. About 90% of patients have sporadic ALS. Zhang et al acta neuropathol commun (2021) 9:75 injury (suggested ALS risk factors [8, 31]) are linked to DNAm [20]. DNAm is closely associated with aging-the strongest risk factor of ALS [3]. The cumulative assessment of DNAm levels at 353 age-related CpGs (constituting DNAm-age) revealed an association of DNAm-age acceleration with disease age of onset, duration or survival in C9orf72-carriers and general ALS patients [35, 36]. DNAm-age is not greatly modulated by genetic variations, because none of the 353 age-related CpGs are mapped to common single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) > 5% [3]

Methods

Results

Discussion

Conclusion