Impact of multiple sclerosis risk alleles on the plasma proteome

<h3></h3> Genetic analysis of multiple sclerosis (MS) susceptibility has implicated over 200 loci, however it remains unclear how genetic variants impact disease pathogenesis. Clarifying how MS-associated genetic variants affect the plasma proteome could help to identify druggable targets and elucidate disease pathobiology. We used summary-data-based Mendelian Randomisation (SMR) to explore the relationship between genetically-determined levels of plasma proteins and MS. We obtained plasma protein quantitative trait data from the UK Biobank Pharma Proteomics Project of 33,000 participants. We obtained summary statistics from the largest and most recent International MS Genetics Consortium GWAS of 14,802 MS and 26,703 control participants. Of 1,865 proteins examined, we found strong evidence supporting causal associations between plasma levels of four proteins and MS risk (PSMR&lt; 5.4 x10–6, PHEIDI &gt; 0.05, αBonferroni&lt;0.01, table 1). Genetically-predicted decreases in FCRL3, CD40, and TNF receptor superfamily member 1A (TNFRSF1A), and genetically-predicted elevation of CD58 were associated with increased MS risk. Colocalisation analysis demonstrated that three are highly likely to be driven by single variants: rs1800694C for TNFRSF1A, rs4810485T for CD40 and rs10801908C for CD58, the latter of which is a novel association. By linking MS risk alleles to changes in plasma proteins we strengthen the theoretical genetic support for pharmacological targeting of these proteins as a strategy for disease modification in MS. Impact of Multiple Sclerosis risk alleles on the plasma proteome