Genetics of multiple sclerosis: lessons from polygenicity.

Autor:	Goris A; KU Leuven, Leuven Brain Institute, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium. Electronic address: an.goris@kuleuven.be., Vandebergh M; KU Leuven, Leuven Brain Institute, Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium., McCauley JL; John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA., Saarela J; Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway; Institute for Molecular Medicine Finland and Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway., Cotsapas C; Departments of Neurology and Genetics, Yale School of Medicine, New Haven, CT, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Neurology [Lancet Neurol] 2022 Sep; Vol. 21 (9), pp. 830-842.
DOI:	10.1016/S1474-4422(22)00255-1
Abstrakt:	Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. Most variants are non-coding and seem to act through cell-specific effects on gene expression and splicing. The likely functions of these variants implicate both adaptive and innate immune cells in the pathogenesis of multiple sclerosis, provide pivotal biological insight into the causes and mechanisms of multiple sclerosis, and some of the variants implicated in multiple sclerosis also mediate risk of other autoimmune and inflammatory diseases. Genetics offers an approach to showing causality for environmental factors, through Mendelian randomisation. No single variant is necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations, and translating these associations into an understanding of the biology of multiple sclerosis. Competing Interests: Declaration of interests AG has received consulting fees from Merck, travel fees from Roche and Merck, and research funding from Novartis and Roche. AG's research is supported by the Research Fund KU Leuven (grant number: C24/16/045), the Research Foundation-Flanders (grant number: FWO GOA7219N), the Belgian Charcot Foundation, multiple sclerosis (MS) Liga Vlaanderen, the Queen Elisabeth Medical Foundation, and the Progressive MS Alliance. JS has received speaker fees and research funding from Sanofi-Genzyme and NovoNordisk. JS is co-founder and minority shareholder of VEIL.AI, a spin off from the University of Helsinki owned by founders and Helsinki University Funds that offers artificial intelligence based anonymisation solutions for safe health data handling and sharing, and has a patent pending on compatible anonymisation of data sets from different sources. JLM has participated in advisory board meetings for Sanofi-Genzyme and received research funding from Genentech, Biogen Idec, and the Bristol-Myers Squibb Foundation. JLM's research is supported by the US National Institutes of Health (grant numbers: R01NS096212, R01NS099240), the Genentech Health Equity Innovation Fund (grant number: G-79758), and the Bristol-Myers Squibb Foundation. CC's research is also supported by the US National Institutes of Health (grant numbers: R01 AI122220, R01 NS106104). MV is a Research Fellow of the Research Foundation-Flanders (grant number: 11ZZZ21N). Research of AG, JS and CC is supported by the Horizon2020 MultipleMS consortium (grant number: EU RIA 733161). (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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