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Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis

View ORCID ProfileBenjamin Meir Jacobs, Thomas Taylor, Amine Awad, David Baker, Gavin Giovanonni, Alastair Noyce, Ruth Dobson
doi: https://doi.org/10.1101/2020.01.20.907451
Benjamin Meir Jacobs
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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Thomas Taylor
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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Amine Awad
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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David Baker
2BartsMS, Blizard Institute, Queen Mary University of London
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Gavin Giovanonni
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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Alastair Noyce
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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Ruth Dobson
1Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London
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  • For correspondence: ruth.dobson@qmul.ac.uk
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Abstract

Background Multiple Sclerosis (MS) is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study (GWAS) findings in MS into therapeutics and effective preventive strategies has been limited to date.

Methods We used Summary Data-Based Mendelian Randomisation (SMR) to synthesise findings from public expression quantitative trait locus (eQTL; eQTLgen and CAGE), methylation quantitative trait locus (mQTL; Lothian Birth Cohort and Brisbane Systems Genetics Study), and MS GWAS datasets (International Multiple Sclerosis Genetics Consortium). By correlating the effects of methylation on MS (M-2-MS), methylation on expression (M-2-E), and expression on MS susceptibility (E-2-MS), we prioritise genetic loci with strong evidence of causally influencing MS susceptibility. We overlay these findings onto a list of ‘druggable’ genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and STRING to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr Virus-infected B cells, Lymphoblastoid Cell Lines (LCLs). We conducted a systematic review of prioritised genes using the Open Targets platform to identify completed and planned trials targeted prioritised genes in MS and related disease areas.

Results Expression of 45 genes in peripheral was strongly associated with MS susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leukocyte signalling. We refined this prioritised gene list by restricting to loci where CpG site methylation was associated with MS susceptibility (M-2-MS), with gene expression (M-2-E), and where expression was associated with MS susceptibility (E-2-MS). This approach yielded a list of 15 prioritised druggable target genes for which there was evidence of a causal pathway linking methylation, expression, and MS. Five of these 15 genes are targeted by existing drugs (CD40, ERBB2, VEGFB, MERTK, and PARP1), and three were replicated in a smaller eQTL dataset (CD40, MERTK, and PARP1). In LCLs, SMR prioritised 7 druggable gene targets, of which only one was priortised by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritised genes in disorders related to MS.

Conclusions We use public datasets and SMR to identify a list of prioritised druggable genetic targets in Multiple Sclerosis. We hope our findings could be translated into effective repurposing of existing drugs to provide novel therapies for MS and, potentially, provide a platform for developing preventive therapies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 25, 2020.
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Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis
Benjamin Meir Jacobs, Thomas Taylor, Amine Awad, David Baker, Gavin Giovanonni, Alastair Noyce, Ruth Dobson
bioRxiv 2020.01.20.907451; doi: https://doi.org/10.1101/2020.01.20.907451
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Summary-data-based mendelian randomisation reveals druggable targets for multiple sclerosis
Benjamin Meir Jacobs, Thomas Taylor, Amine Awad, David Baker, Gavin Giovanonni, Alastair Noyce, Ruth Dobson
bioRxiv 2020.01.20.907451; doi: https://doi.org/10.1101/2020.01.20.907451

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