Abstract
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.
Highlights
Multiple sclerosis (MS; MIM 126200) is an autoimmune disease of the central nervous system and a common cause of neurologic disability in young adults (Compston and Coles, 2008)
In our most recent meta-analysis of 14,802 MS cases and 26,703 controls, these effects—including 32 mapping to classical human leukocyte antigen (HLA) alleles and other variation in the major histocompatibility (MHC) locus (International Multiple Sclerosis Genetics Consortium et al, 2017; Moutsianas et al, 2015; Patsopoulos et al, 2013)—account for 7.5% of h2g, the heritability attributable to additive genetic effects captured by genotyping arrays, with a total of 19.2% of h2g attributable to all common variants in the autosomal genome (International Multiple Sclerosis Genetics Consortium et al, 2017)
Complex diseases where large genomewide association studies (GWASs) have been conducted, we find that common variants account for the bulk of trait heritability, they cannot account for its entirety
Summary
Multiple sclerosis (MS; MIM 126200) is an autoimmune disease of the central nervous system and a common cause of neurologic disability in young adults (Compston and Coles, 2008) It is most prevalent in individuals of northern European ancestry and—in line with other complex, common disorders—shows substantial heritability (Binder et al, 2016), with a sibling standardized incidence ratio of 7:1 (Westerlind et al, 2014). We have found no evidence that mutations in individual families drive disease risk in genome-wide linkage analyses of 730 MS families with multiple affected members (Sawcer et al, 2005) These results indicate that neither epistasis between known risk variants nor mutations in a limited number of loci are major sources of MS risk. They do not, preclude a role for variants present in the population at low frequencies, which cannot be imputed but are likely to individually contribute moderate risk
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