The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility

Abstract

was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/143933 doi: bioRxiv preprint first posted online Jul. 13, 2017; 2 Abstract:We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain-resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.

Factors associated with and long-term outcome of benign multiple sclerosis: a nationwide cohort study

“…Data for 5698 cases were available. Participants were asked to give blood samples, which were genotyped on an Illumina custom array, the MS replication chip 14. Genotypes in the major histocompatibility complex region from the custom array were used to impute human leucocyte antigen ( HLA)-DRB1 and HLA-A alleles with HLA*IMP02 ,15 described in detail elsewhere 16.…”

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

“…The first GWAS in MS was completed by the International Multiple Sclerosis Genetics Consortium (IMSGC) on subjects from the US and UK using an unorthodox family-based (MS patients and both parents) study design for discovery coupled with case-control replication [41]. A number of GWAS and large-scale targeted studies followed in the ensuing 10 years [42–48], culminating in the collation of a genetic dataset representing 47,351 MS subjects and 68,284 controls that showed unequivocal statistical evidence for the association of 200 autosomal susceptibility variants outside the MHC, one chromosome X variant, and 32 independent associations within the extended MHC [49]. Altogether, different measures of the heritability explained by all associations are still in the 20–30% range, of which a substantial proportion can be assigned to the MHC region.…”

“…For each tissue, the proportion of SNPs in the list that were located on DHS regions to the proportion of all SNPs located on DHS regions active in that tissue were compared. Notably, statistically significant enrichment was observed only in 9 cells from the immune system, including CD3, CD4, CD8 (T cells), CD14 (monocytes) and CD19 (B cells) [49]. This finding highlights the immune nature of genetic MS susceptibility.…”

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

“…Major histocompatibility complex (MHC) genes are by far the most important MS genetic susceptibility factors, with HLA‐DRB1*15:01 allele conferring the highest risk in Caucasians (International Multiple Sclerosis Genetics Consortium [IMSGC] et al, ; Schmidt, Williamson, & Ashley‐Koch, ). With the advent of genome‐wide association studies (GWAS), the past decade has seen a tremendous success in identifying 200 additional novel risk polymorphisms in 157 regions outside the MHC that, together with 32 independent associations within the extended MHC region, explain up to 39% of the heritability of the disease (Baranzini & Oksenberg, ; IMSGC et al, ). The majority of established MS risk variants are located within genes linked to leucocyte activation and function, emphasizing the prominent role of aberrant immune responses in the development of neuroinflammation, demyelination and axonal degeneration (Dendrou et al, ; Yadav, Mindur, Ito, & Dhib‐Jalbut, ).…”

“…To the best of our knowledge, although the majority of studies that examined the association between TNFRSF1A polymorphisms and MS were performed in Caucasians of European ancestry (De Jager et al, ; Goris et al, ; Hoffjan et al, ; IMSGC et al, ; IMSGC, ; Jenne et al, ; Kümpfel et al, ; Patsopoulos et al, ; Swaminathan et al, ), only very little is known about the role of TNFRSF1A variants in susceptibility to MS in Slavic populations of Central, Eastern or South‐Eastern Europe. Recently, a study in Russians failed to replicate individual associations of the two TNFRSF1A SNPs with MS, suggesting possible interpopulation differences in the genetic background of the disease (Bashinskaya et al, ).…”