Objectives To identify genes that confer MS risk via the alteration of cis‐regulated protein abundance and verify their aberrant expression in human brain. Methods Utilizing a two‐stage proteome‐wide association study (PWAS) design, MS GWAS data ( N = 41,505) was respectively integrated with two distinct human brain proteomes from the dorsolateral prefrontal cortex, including ROSMAP ( N = 376) in the discovery stage and Banner ( N = 152) in the confirmation stage. In the following, Bayesian colocalization analysis was conducted for GWAS and protein quantitative trait loci signals to prioritize candidate genes. Differential expression analysis was then used to verify the dysregulation of risk genes in white matter and gray matter for evidence at the transcription level. Results A total of 51 genes whose protein abundance had association with the MS risk were identified, of which 18 genes overlapped in the discovery and confirmation PWAS. Bayesian colocalization indicated six causal genes with genetic risk variants for the MS risk. The differential expression analysis of SHMT1 ( P FDR = 4.82 × 10 −2 ) , FAM120B ( P FDR = 8.13 × 10 −4 ) in white matter and ICA1L ( P FDR = 3.44 × 10 −2 ) in gray matter confirmed the dysregulation at the transcription level. Further investigation of expression found SHMT1 significantly up‐regulated in white matter lesion, and FAM120B up‐regulated in both white matter lesion and normal appearing white matter . ICA1L was down‐regulated in both gray matter lesion and normal appearing gray matter. Interpretation Dysregulation of SHMT1, FAM120B and ICA1L may confer MS risk. Our findings shed new light on the pathogenesis of MS and prioritized promising targets for future therapy research.

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.