Summary: Researchers have identified three genes whose altered protein expression in the brain appears linked to multiple sclerosis and may point to new avenues for understanding disease mechanisms and developing treatments.
Source: Wiley
New research published in the Annals of Clinical and Translational Neurology has highlighted three genes and their corresponding proteins—SHMT1, FAM120B and ICA1L—that are potentially involved in the development and progression of multiple sclerosis (MS).
The study used large-scale genetic and proteomic data to compare protein abundance and gene expression in brain tissue from individuals with MS and controls. The investigators found consistent differences in the expression of SHMT1, FAM120B and ICA1L across multiple brain datasets, suggesting these genes may play a role in MS pathogenesis.
Investigating how these genes influence cellular pathways in the brain could reveal underlying mechanisms that drive MS onset and progression, and may help prioritize targets for future therapeutic development.
“These findings add important evidence about MS biology and prioritize promising targets for follow-up studies into therapies,” the authors note.
About this genetics and multiple sclerosis research news
Author: Sara Henning-Stout
Source: Wiley
Contact: Sara Henning-Stout – Wiley
Image: The image is in the public domain
Original Research: Open access.
Title: Brain proteome-wide association study linking-genes in multiple sclerosis pathogenesis by Tingting Jia et al., Annals of Clinical and Translational Neurology
Abstract
Brain proteome-wide association study linking-genes in multiple sclerosis pathogenesis
Objectives
The study aimed to identify genes that increase MS risk by changing locally regulated (cis) protein abundance in the brain and to confirm whether these genes show abnormal expression in human brain tissue.
Methods
The researchers used a two-stage proteome-wide association study (PWAS) approach. They combined summary statistics from a large MS genome-wide association study (GWAS; N = 41,505) with two independent human dorsolateral prefrontal cortex proteomes. The discovery analysis used the ROSMAP proteome (N = 376) and the confirmation analysis used the Banner proteome (N = 152). To refine candidate genes, Bayesian colocalization was performed to determine whether GWAS signals and protein quantitative trait loci (pQTL) shared the same causal variants. Finally, differential expression analyses tested whether the prioritized genes were dysregulated at the RNA level in white and gray matter.
Results
Across the analyses, 51 genes were identified whose protein abundance associated with MS risk. Of these, 18 genes were detected in both the discovery and confirmation PWAS stages. Bayesian colocalization prioritized six genes with evidence that genetic risk variants influence protein levels linked to MS risk. Differential expression analysis provided transcriptional support for three genes in brain tissue: SHMT1 (P_FDR = 4.82 × 10−2) and FAM120B (P_FDR = 8.13 × 10−4) showed altered expression in white matter, while ICA1L (P_FDR = 3.44 × 10−2) was dysregulated in gray matter. Further tissue-specific examination revealed that SHMT1 was significantly up-regulated in white matter lesions, FAM120B was up-regulated in both white matter lesions and normal-appearing white matter, and ICA1L was down-regulated in both gray matter lesions and normal-appearing gray matter.
Interpretation
The combined proteomic and transcriptomic evidence supports the notion that dysregulation of SHMT1, FAM120B and ICA1L may contribute to MS susceptibility and disease biology. Identifying these genes helps to clarify molecular pathways potentially involved in MS and highlights specific targets that warrant further functional study and therapeutic exploration.
Taken together, this study demonstrates the value of integrating large-scale genetic, proteomic and transcriptional data from human brain tissue to prioritize biologically relevant genes in complex neurological disorders. Future work will need to determine the exact cellular processes affected by SHMT1, FAM120B and ICA1L, and whether modifying their expression or protein activity could influence disease course or serve as a basis for new treatments.