Integrated multi-omics analysis identifies novel risk loci for amyotrophic lateral sclerosis in the Chinese population

DNA methylation can serve as proxies of (past) exposures and disease progression, as well as provide clues to reveal the pathogenesis of amyotrophic lateral sclerosis (ALS) from the perspective of gene-environment interactions. Here, we conducted an epigenome-wide DNA methylation analysis in peripheral blood cells from 480 cases of ALS (203 had survival data) and 207 health controls of Han Chinese ancestry (Peking University Third Hospital ALS cohort, PUTH-ALS), whose genomic DNA methylation patterns were quantified using an Illumina Infinium Human Methylation450 Bead Chip. After rigorous quality control, we identified a number of differentially methylated positions (DMPs), 5 of which were of high confidence hypermethylated biomarkers in the PUTH-ALS cases, annotating to the genes ANKLE2 , SSH2 , CDC42BPB , ELAVL3 , and CLEC14A . These five genes showed suppressed gene expression in the postmortem brain tissue expression profile from the New York Genomic Center ALS cohort. Furthermore, 3 DMPs ( RRP1B , IL17RD , and FBXO11 ) associated with survival time in ALS cases were identified, suggesting that they could represent indicators of underlying disease processes potentially amenable to therapeutic interventions. We also identified a 27-loci signature that serves as an assessment of the risk of ALS based on abnormal methylation patterns, which has great potential to advance early clinical diagnosis in ALS (AUC of 0.861). Our study provides strong evidences that DNA methylation plays an important role in ALS pathogenesis, and the observed DNA methylation aberrations could potentially serve as valuable references for identifying diagnostic biomarkers.