Abnormal brain protein abundance and mRNA expression of SARM1 in amyotrophic lateral sclerosis

Abstract There is an urgent need to identify additional causal genes utilizing innovative methodologies due to the limits of the existing identified disease-associated genes in explaining the etiology of amyotrophic lateral sclerosis (ALS). In this study, the abnormal protein abundance in the human brain was used to identify the ALS risk genes and their aberrant expression was verified in multiple tissues. We conducted a two-stage proteome-wide association study (PWAS) using the ALS genome-wide association study (GWAS) data and two distinct human brain protein quantitative trait loci (pQTL). To further support the PWAS risk genes, we also performed colocalization followed by differential expression analysis on lower motor neuron, skeletal muscle, and whole blood samples. Six ALS risk genes (SCFD1, SARM1, TMEM175, BCS1L, WIPI2, and DHRS11) were found during the PWAS discovery phase, and two of them (SARM1 and BCS1L) were confirmed during the validation phase. The following Bayesian colocalization analysis supported SARM1 had causal gene that drove both of the pQTL and GWAS signals. Further differential expression analysis revealed that SARM1 was markedly down-regulated in lower motoneurons, skeletal muscle, and whole blood tissues. Our findings supported the existence of ALS-related risk genes and identified many promising protein candidates for the future investigation of therapeutic targets. The dysregulation of SARM1 in multiple tissues provides a new direction to explain the ALS pathology and the clinical manifestations of muscle weakness in ALS patients.