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Disentangling multiple sclerosis phenotypes through Mendelian disorders: A network approach. | LitMetric

Disentangling multiple sclerosis phenotypes through Mendelian disorders: A network approach.

Mult Scler

Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy Neuroimmunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.

Published: March 2024

AI Article Synopsis

Article Abstract

Background: The increasing knowledge about multiple sclerosis (MS) pathophysiology has reinforced the need for an improved description of disease phenotypes, connected to disease biology. Growing evidence indicates that complex diseases constitute phenotypical and genetic continuums with "simple," monogenic disorders, suggesting shared pathomechanisms.

Objectives: The objective of this study was to depict a novel MS phenotypical framework leveraging shared physiopathology with Mendelian diseases and to identify phenotype-specific candidate drugs.

Methods: We performed an enrichment testing of MS-associated variants with Mendelian disorders genes. We defined a "MS-Mendelian network," further analyzed to define enriched phenotypic subnetworks and biological processes. Finally, a network-based drug screening was implemented.

Results: Starting from 617 MS-associated loci, we showed a significant enrichment of monogenic diseases ( < 0.001). We defined an MS-Mendelian molecular network based on 331 genes and 486 related disorders, enriched in four phenotypic classes: neurologic, immunologic, metabolic, and visual. We prioritized a total of 503 drugs, of which 27 molecules active in 3/4 phenotypical subnetworks and 140 in subnetwork pairs.

Conclusion: The genetic architecture of MS contains the seeds of pathobiological multiplicities shared with immune, neurologic, metabolic and visual monogenic disorders. This result may inform future classifications of MS endophenotypes and support the development of new therapies in both MS and rare diseases.

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http://dx.doi.org/10.1177/13524585241227119DOI Listing

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