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Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ ( n =21 856) and multiple sclerosis (MS) ( n =43 879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD ( n =16 731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

The prevalence of multiple sclerosis (MS) is increasing, and the presence of a latitude gradient for MS risk is still discussed. We present the first nationwide prevalence estimates for Norway, spanning the latitudes from 58–71 degrees North, in order to identify a possible latitude gradient. Information from the Oslo MS Registry and the Norwegian MS Registry and Biobank was combined with data from the Norwegian Patient Registry, the Norwegian Prescription Database and Statistics Norway. We estimated a crude prevalence of 203/100,000 on 1 January 2012. The prevalence in the Northern and Southern regions were not significantly different. MS prevalence in Norway is among the highest reported worldwide. We found no evidence of a latitude gradient.

Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31 . Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA , IL21R and IL4R . We tested the association with multiple sclerosis (MS) in a Nordic case–control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-γ (IFN-γ) and TNF in cerebrospinal fluid of MS patients. In IL21R , there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-γ expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.

Background Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. Methods RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.

Genome-wide association studies have revealed that the 16p13 chromosomal region, including CLEC16A , DEXI, CIITA and SOCS1 , is associated with susceptibility to autoimmune diseases. As non-coding single-nucleotide polymorphisms (SNPs) may confer susceptibility to disease by affecting expression of nearby genes, we examined whether autoimmune-associated intronic CLEC16A SNPs (rs12708716, rs6498169 and rs7206912) correlate with the expression of CLEC16A itself as well as neighboring genes in whole-blood and thymic samples. Real-time quantitative PCR analyses show that SOCS1 and DEXI expression was lower in thymic samples carrying at least one of the CLEC16A risk alleles compared with non-carriers of the risk allele. Linear regression analysis revealed a significant correlation between the expression level of CLEC16A and that of SOCS1 and DEXI in thymic samples. These data indicate a possible regulatory role for multiple sclerosis-associated non-coding CLEC16A SNPs and a common control mechanism for the expression of CLEC16A , SOCS1 and DEXI .

Background Inconsistent results have been obtained with regard to headache comorbidity in multiple sclerosis (MS). Objective Investigate the one-year prevalence of migraine and tension-type headache (TTH) in Norwegian MS patients and relate this to clinical parameters. Methods A questionnaire concerning headache was administered to 756 MS patients and 1090 controls and used to determine the one-year prevalence of migraine and frequent TTH. Results No significant differences were seen between patients and controls or between patients with different disease course. Less migraine was observed in patients with Expanded Disability Status Scale score (EDSS) ≥4.0. Conclusions This case-control study does not support an association between migraine or TTH and MS.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified—1q11–24, 2q24–32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21–22, 6q21, 9q34.3, 10p15, 10p12–13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12–13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Objectives Oslo, the capital of Norway, has a high prevalence of multiple sclerosis (MS). In recent decades there has been substantial immigration to Oslo from Asia, the Middle East and Africa. The aim of the study was to estimate the prevalence of MS among non-Western immigrants living in Oslo, adjusted for duration of residence. Methods Data were obtained from the MS registry at Ullevål University Hospital. The prevalence of MS was adjusted for ethnicity, age and duration of residence in Norway. Results A total of 786 definite MS patients were alive and resident in Oslo on 31 December 2005, yielding a crude prevalence of 148/10 5 . Twentyseven patients were of non-Western origin: Middle East 14, Asia 9, Africa 4. The non-Western patients' mean age at migration was 20. The crude prevalence (95 % CI) of MS patients was 170/10 5 (159–182) for the Norwegian/Western, 85/10 5 (50–143) for the Middle East, 21/10 5 (11–41) for the Asian, and 20/10 5 (7–53) for the African cohorts. The high MS prevalence in the Middle East cohort and the low prevalence among Asian/African immigrants were also pronounced after adjustment for age and duration of residence. Conclusions The Middle East immigrants had a markedly higher prevalence of MS despite a shorter duration of residence than other non-Western patients. These findings suggest that people from the Middle East have a greater genetic disposition for MS. Furthermore, the high age at migration among the non-Western immigrants indicates that possible environmental factors affecting MS risk may also act on adults.

In an attempt to map chromosomal regions carrying rare gene variants contributing to the risk of multiple sclerosis (MS), we identified segments shared identical-by-descent (IBD) using the software BEAGLE 4.0's refined IBD analysis. IBD mapping aims at identifying segments inherited from a common ancestor and shared more frequently in case-case pairs. A total of 2106 MS patients of Nordic origin and 624 matched controls were genotyped on Illumina Human Quad 660 chip and an additional 1352 ethnically matched controls typed on Illumina HumanHap 550 and Illumina 1M were added. The quality control left a total of 441 731 markers for the analysis. After identification of segments shared by descent and significance testing, a filter function for markers with low IBD sharing was applied. Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS. However, all markers but for one were located telomerically, including the very distal markers. For methodological reasons, such segments have a low sharing of IBD signals and are prone to be false positives. One marker on chromosome 19 reached genome-wide significance and was not one of the distal markers. This marker was located within the GNA11 gene, which contains no previous association with MS. We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.