SummaryMultiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in signi cant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults. To provide insight into the mechanisms determining progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our ndings in a further 9,805 cases. We identi ed a signi cant association with rs10191329 in the DYSF-ZNF638 locus (P=3.6×10-9), the risk allele shortening the median time to require a walking aid by up to 3.7 years. We also identi ed suggestive association with rs149097173 in the DNM3-PIGC locus (P=2.3×10-7) and signi cant enrichment for expression in CNS tissues. Mendelian randomization analyses indicated a protective role for higher educational attainment. In contrast to immune-driven susceptibility, these ndings indicate a key role of CNS resilience and neurocognitive reserve in determining outcome in MS.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways ( PLAU , MASP1 , C2 ), inflammasome assembly ( NLRP12 ), Wnt signaling ( UBR2 , CTNNA3 , NFATC2 , RNF213 ), nuclear receptor complexes ( NCOA3 ), and cation channels and exchangers ( KCNG4 , SLC24A6 , SLC8B1 ). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-β (IFNβ) (4-year follow-up). We performed a genome-wide association study in 337 IFNβ-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNβ-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNβ stimulation in HC (P=3.1 × 10 and 5.6 × 10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460); moreover, TBXAS1 appeared downregulated upon IFNβ administration (β=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNβ.