Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter ...including chromosome 13q31–32 and the Glypican-5 and Glypican-6 genes. In order to further explore the 13q31–32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (pcorr = 0.006). Thus, this study supports that MS susceptibility at 13q31–32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.
Abstract Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles ...and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n = 3876). Specific KIR ligands were associated with patients when compared to controls (n = 3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.
The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes ...among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic ...neurological disability in young adults
. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility
, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.
Multiple 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.
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•Almost 20% of MS risk heritability can be attributed to common genetic variants•We show that nearly 5% of heritability is explained by coding low-frequency variants•We identify four novel genes driving risk independently of common-variant signals•These genes would not have been found by common-variant studies
In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology.
Abstract Brain-derived neurotrophic factor (BDNF) has been proposed a protective role in multiple sclerosis (MS) in several studies. The val66 met polymorphism alters the function of the BDNF ...protein, and has along with rs56164415 previously been reported to be associated with MS. We genotyped BDNF SNPs val66 met and rs56164415 in 2149 Norwegian MS patients and 2747 healthy controls. No association was found for any of the SNPs to disease susceptibility or any clinical or demographic parameters including sex, age at onset, disease course, disease severity and cognitive impairment.
Abstract Recently, several non-HLA loci have been shown to be convincingly associated with Multiple Sclerosis (MS) susceptibility, assumingly indicating important pathways in the pathogenesis. A ...genotype influence on disease outcome measures by these genes would support a role of these pathways in ongoing tissue damage. Here, however, we report a consistent dissociation between causation and progression for five non-HLA genotypes ( IL7R , IL2RA, CLEC16A, CD226 and SH2B3 ) in 1776 Scandinavian MS patients.
Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified ...several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00-1.13)) in a large Scandinavian case-control study of 5367 MS patients and 4485 controls. The expression of KLRB1 in blood from MS patients was higher compared with healthy controls (P<0.001), and the KLRB1 expression decreased significantly (P<0.001) after interferon (IFN)-β treatment. KLRB1 was expressed in T and natural killer (NK) cells, and expression mainly decreased in NK cells in patients treated with IFN-β. Collectively, our results indicate that KLRB1 gene expression is altered in MS and likely to be involved in the pathogenesis of the disease, whereas rs4763655 in KLRB1 seems to have a minimal role in MS susceptibility.
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS ...patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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