Genes associated with grey matter volume reduction in multiple sclerosis.

Area of Science:

• Neuroscience
• Genetics
• Neuroimmunology

Background:

• Multiple sclerosis (MS) is characterized by significant grey matter volume (GMV) reduction, contributing to cognitive impairment.
• While genome-wide association studies (GWASs) have identified numerous MS-associated genes, their specific roles in GMV reduction and cognitive decline remain unclear.

Purpose of the Study:

• To identify genes associated with GMV reduction in multiple sclerosis (MS).
• To investigate the functional and expression characteristics of these identified genes in relation to MS pathology and cognitive function.

Main Methods:

• Performed cross-sample partial least squares regression using gene expression data from postmortem brains and GMV differences in MS patients from meta-analyses and direct comparisons.
• Utilized a discovery phase with 1473 brain tissue samples and a replication phase comparing 69 MS patients with 70 controls.
• Analyzed gene enrichment for MS-related GWAS genes, functional pathways, cell-type specificity, and expression levels (upregulated vs. downregulated).

Main Results:

• Identified 623 genes significantly associated with GMV reduction in MS.
• These genes are enriched for MS GWAS findings, functionally linked to ion channels, synaptic transmission, and neuronal projections, with higher expression in neurons.
• A significant enrichment of downregulated genes was observed, and their spatial expression correlated with brain activation patterns in memory and language tasks.

Conclusions:

• Grey matter atrophy in MS likely results from the combined effects of multiple MS-associated genes.
• Downregulated gene expression, particularly in neurons, plays a crucial role in MS-related grey matter reduction and cognitive deficits.
• These findings highlight specific genetic pathways involved in MS neurodegeneration and cognitive impairment.