Pathway Analysis of Two Amyotrophic Lateral Sclerosis GWAS Highlights Shared Genetic Signals with Alzheimer's Disease and Parkinson's Disease

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disease after Alzheimer's disease (AD) and Parkinson's disease (PD). In order to unravel more genetic etiology of ALS, genome-wide association studies (GWAS) have been conducted. However, the newly identified ALS susceptibility loci exert only very small risk effects and cannot fully explain the underlying ALS genetic risk. A large proportion of the heritability of ALS is still to be explained. Recently, pathway analysis of GWAS has been used to investigate the mechanisms of AD and PD. We think that AD or PD risk pathways may also be involved in ALS. In order to confirm this view, we conducted a pathway analysis of two independent ALS GWAS. We identified multiple classifications of the Kyoto Encyclopedia of Genes and Genomes pathways related to metabolism, immune system and diseases, environmental information processing, genetic information processing, cellular processes, and nervous system and neurodegenerative diseases to be the consistent signals in the two ALS GWAS. On the single pathway level, we identified 12 shared pathways. We compared the findings from ALS GWAS with those of previous pathway analyses of AD and PD GWAS. The results further supported the involvement of AD and PD risk pathways in ALS. We believe that our results may advance the understanding of ALS mechanisms and will be very useful for future genetic studies.