表型
孟德尔遗传
多发性硬化
内表型
疾病
生物
联机孟德尔在人类中的遗传
计算生物学
遗传学
遗传建筑学
生物信息学
神经科学
基因
医学
免疫学
认知
病理
作者
Gianmarco Bellucci,Maria Chiara Buscarinu,Roberta Reniè,Virginia Rinaldi,Rachele Bigi,Rosella Mechelli,Silvia Romano,Marco Salvetti,Giovanni Ristori
标识
DOI:10.1177/13524585241227119
摘要
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 ( p < 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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