Multiomics integration prioritizes potential drug targets for multiple sclerosis

Significance

We tested hundreds of multiple sclerosis (MS)-associated proteins in plasma and brain and confirmed the potential causal role of 18 proteins (9 in plasma and 9 in brain) through comprehensive analytical strategies. We revealed intricate interactions between seven of these 18 proteins and 19 known MS drug targets, as well as interactions among 11 of these 18 proteins within and across plasma and brain. Furthermore, we identified 16 existing non-MS drugs targeting six of these 18 potential targets. These findings present significant potential for both the discovery of new drugs and the repurposing of existing ones. The reliability of our findings was further supported by 78 annotated pathways, transcriptional evidence on six targets, and external validation on 10 targets.

Abstract

Multiple sclerosis (MS) is an immune-mediated disease with no current cure. Drug discovery and repurposing are essential to enhance treatment efficacy and safety. We utilized summary statistics for protein quantitative trait loci (pQTL) of 2,004 plasma and 1,443 brain proteins, a genome-wide association study of MS susceptibility with 14,802 cases and 26,703 controls, both bulk and cell-type specific transcriptome data, and external pQTL data in blood and brain. Our integrative analysis included a proteome-wide association study to identify MS-associated proteins, followed by summary-data-based Mendelian randomization to determine potential causal associations. We used the HEIDI test and Bayesian colocalization analysis to distinguish pleiotropy from linkage. Proteins passing all analyses were prioritized as potential drug targets. We further conducted pathway annotations and protein–protein interaction network analysis (PPI) and verified our findings at mRNA and protein levels. We tested hundreds of MS-associated proteins and confirmed 18 potential causal proteins (nine in plasma and nine in brain). Among these, we found 78 annotated pathways and 16 existing non-MS drugs targeting six proteins. We also identified intricateAQ PPIs among seven potential drug targets and 19 existing MS drug targets, as well as PPIs of four targets across plasma and brain. We identified two targets using bulk mRNA expression data and four targets expressed in MS-related cell types. We finally verified 10 targets using external pQTL data. We prioritized 18 potential drug targets in plasma and brain, elucidating the underlying pathology and providing evidence for potential drug discovery and repurposing in MS.

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