Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells.

Melissa M Gresle,Judith Field,Helmut Butzkueven,Terence P Speed,Jac Charlesworth,Bruce Taylor,Letitia D Smith,Jim Stankovich,Alan G Baxter,Alison Hamlett,Melanie Bahlo,Josephine Baker,Vilija G Jokubaitis,Laura J Johnson,Jodi Haartsen,Louise Laverick,Margaret A Jordan,Tim Spelman,Matthew A Brown

doi:10.26508/lsa.202000650

Abstract

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.

Highlights

Multiple Sclerosis (MS) is an autoimmune disease causing multifocal central nervous system inflammatory demyelination and axonal injury
More recent genome-wide association studies have identified at least 200 single nucleotide polymorphisms (SNPs) outside of the MHC region that are associated with multiple sclerosis (MS) risk (International Multiple Sclerosis Genetics Consortium et al 2011, 2013, 2019; )
We comprehensively investigated transcriptional changes associated with MS risk SNPs in recirculating leukocytes

Summary

Introduction

Multiple Sclerosis (MS) is an autoimmune disease causing multifocal central nervous system inflammatory demyelination and axonal injury. More recent genome-wide association studies have identified at least 200 single nucleotide polymorphisms (SNPs) outside of the MHC region that are associated with MS risk (International Multiple Sclerosis Genetics Consortium et al 2011, 2013, 2019; ). These SNPs are all common (>2.1% risk allele frequency), are present in unaffected individuals, and have small odds ratios of between 0.8 and 1.3, representing both protective and risk variants. Carriage of these common genetic variants is unlikely to be sufficient or necessary for the pathogenesis of disease

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