Multiomics integration prioritizes potential drug targets for multiple sclerosis

Area of Science:

• Genetics and Genomics
• Neuroimmunology
• Pharmacology

Background:

• Multiple sclerosis (MS) is an immune-mediated neurological disorder lacking a definitive cure.
• Enhancing treatment efficacy and safety through novel drug discovery and repurposing is critical for managing MS.
• Understanding the genetic and proteomic underpinnings of MS is essential for identifying new therapeutic targets.

Purpose of the Study:

• To identify potential causal proteins associated with multiple sclerosis (MS) susceptibility using integrated omics data.
• To explore the utility of these identified proteins as targets for drug discovery and repurposing in MS.
• To elucidate the molecular pathways and interactions involved in MS pathogenesis.

Main Methods:

• Integrative analysis of genome-wide association study (GWAS) data, protein quantitative trait loci (pQTL) from plasma and brain, and transcriptome data (bulk and cell-type specific).
• Proteome-wide association study (PWAS) and summary-data-based Mendelian randomization (SMR) to identify and assess causality of MS-associated proteins.
• HEIDI and Bayesian colocalization analyses to differentiate pleiotropy from linkage, followed by pathway and protein-protein interaction (PPI) network analysis.

Main Results:

• Identified 18 potential causal proteins for MS, with nine each in plasma and brain, through rigorous statistical analyses.
• Annotated 78 pathways and identified 16 existing non-MS drugs targeting six of the prioritized proteins, suggesting repurposing opportunities.
• Revealed intricate protein-protein interactions (PPIs) among potential drug targets and existing MS drugs, highlighting interconnected biological networks.

Conclusions:

• Prioritized 18 proteins in plasma and brain as potential therapeutic targets for multiple sclerosis (MS).
• Provided evidence for drug repurposing by linking identified targets to existing medications and exploring PPI networks.
• This research offers a foundation for developing novel therapeutic strategies and improving existing treatments for MS by elucidating underlying molecular mechanisms.