Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome characterized by the progressive loss of motor neurons in the brain and spinal cord, resulting in muscle weakness, atrophy, and difficulty breathing. ALS shares pathobiological features with spinal atrophy (SA) and hereditary motor neuronopathy (HMN). While only 5-10% of ALS patients have a family history, twin studies estimate the heritability of ALS to be between 38% and 85%, indicating that genetic factors play a significant role in the development of ALS. The most common causal gene in Europe is C9orf72, while SOD1 is the most common in China, highlighting the variability of genetic factors among populations. Recent genetic studies have identified over 100 genes associated with ALS, including causative, associated, susceptibility, and modifying genes. However, only 7.2% to 9.5% of heritability can be explained by genome-wide SNP data, indicating that the majority of the mechanisms behind ALS remains unclear.

To better understand ALS, we employed whole-genome sequencing (WGS) and bioinformatic approaches to investigate the pathogenicity of different types of variants, genetic characteristics of ALS and other neurological disorders with similar phenotypes, and RNA editing events in ALS. We performed WGS on 40 ALS pedigrees and screened for SNV/INDEL/SV/CNV/STR in the entire genome. We found a testing ratio of 32% and identified a causative STR in ATXN2. We also discovered that the pathogenicity mode of variants in the SOD1 gene is associated with the interaction of each amino acid position, and we identified a greater percentage of variant combinations than previously reported. Our findings suggest that WGS is a better choice for ALS genetic testing. We then assembled causal genes from OMIM and risk genes from recent GWAS studies and performed an enrichment in single-cell RNA data of the human brain and spinal cord. We characterized the expression spectrum of ALS-risk genes that are strictly required in motor neurons, as well as the causal genes that demonstrated to be loss-of-function genes. Our results indicate that these genes are dosage-sensitive and may be involved in a lossof-function mechanism for ALS. We also showed heterogeneity of causal genes among ALS, SCA, HMN, SPG, and SMA, as well as a heterogeneity of involved cell types in the brain/spinal cord. Finally, we investigated RNA-editing events in ALS patients and other groups using RNA data from the frontal cortex and motor cortex. We found that ALS patients carried a huge number of RNA-editing sites either in the frontal cortex or in the motor cortex. The frontal cortex is more important for ALS than the motor cortex. Our findings suggest that RNA-editing plays a key role in disease development and progress.