The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 x 10(-10)). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P ¼ 0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P ¼ 0.03 and OR 1.15; P ¼ 0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Description Functions for simple fixed and random effects meta-analysis for two-sample comparisons and cumulative meta-analyses. Draws standard summary plots, funnel plots, and computes summaries and tests for association and heterogeneity.Title Meta-AnalysisLicense GPL-2Imports grid, stats, graphics Examples library(rmeta) data(catheter) a <-meta.MH(n.trt, n.ctrl, col.trt, col.ctrl, data=catheter, names=Name, subset=c (13,6,5,3,7,12,4,11,1,8,10,2)) b <-meta.DSL(n.trt, n.ctrl, col.trt, col.ctrl, data=catheter, names=Name,subset=c (13,6,5,3,7,12,4,11,1,8,10,2)) a b summary(a) summary ( DetailsThis meta-analysis, if done, would likely have resulted in the treatment being widely used a decade earlier than it was, saving many lives. The graph is part of the logo of the Cochrane Collaboration, a group aiming to perform systematic reviews of the entire clinical trial literature. Cumulative meta-analysis of binary data DescriptionA cumulative meta-analysis plot shows how evidence has accumulated over time. The ith line in the cumulative meta-analysis plot is the summary produced by a meta-analysis of the first i trials.Usage cummeta(ntrt, nctrl, ptrt, pctrl, conf.level = 0.95, names = NULL, data= NULL, subset = NULL, na.action = na.fail, method = c("meta.MH", "meta.DSL"), statistic = "OR") cummeta.summaries(effects,stderrs, conf.level = 0.95, names = NULL,weights=NULL, data= NULL, subset = NULL, na.action = get(getOption("na.action")), method = c("fixed", "random"), logscale=TRUE) ## S3 method for class meta.cum plot(x, conf.level = NULL, colors = meta.colors(), xlab = NULL, summary.line = TRUE, summary.conf = FALSE, main="Cumulative meta-analysis", lwd=1, ...) ## S3 method for class meta.cum summary (object ,conf.level=NULL,...)

To investigate the parental relationship of patients with multiple sclerosis (MS) from an extended pedigree with extensive genealogical information up to the middle of the 18th century. Design: Multiple sclerosis is a complex disease resulting from genetic and environmental factors. Parent-oforigin effect, a phenomenon when the same allele may express differently depending on the sex of the transmitting parent, may influence the risk for MS. We investigated parental relationships between patients with MS using extensive genealogical information available from the Genetic Research in Isolated Populations program. We compared the average kinship of the parents of MS patients. We further explored the distribution of shortest genealogical links between parents of MS patients. Subjects: Twenty-four MS patients from the isolated population who could be linked within a large complex pedigree, including 2471 people in total. Results: The results consistently indicate a higher prevalence of maternal transmission of MS. The kinship between mothers of patients was 3.8 times higher than that between fathers (bootstrap P=.01). Among the 814 shortest connections between parents, 333 were maternal (40.9%, vs 25.0% expected), 98 were paternal (12.0%, vs 25.0% expected), and 383 were maternal-paternal (47.1%, vs 50.0% expected) (PϽ .001). Conclusions: Mothers of MS patients were more closely related than their fathers. This skewed relationship shows evidence for a maternal effect in MS. The most likely explanation is a gene-environment effect that takes place in utero.

Multiple sclerosis (MS) is a complex disease with a substantial, yet poorly identified, genetic influence. We estimated the pattern of familial aggregation of MS in a recent genetically isolated population in The Netherlands. Forty-eight MS patients were identified. Their relationship was evaluated by tracing extended pedigrees, making use of municipal and church records. Of the 48 MS patients, 24 could be linked to a common ancestor in 14 generations. However, multiple relationships exist between patients and, to take these into account, we calculated inbreeding and kinship coefficients. We found that MS patients from the isolate were significantly more often related to each other and significantly more often inbred than a non-MS control group, drawn from the same isolate. There was no clustering of Type 1 diabetes and autoimmune thyroid diseases in families of MS patients from this isolate. Finally, HLA typing was performed. Although there was a trend towards a higher prevalence of the HLA DRB1*15 allele in patients compared to controls, differences did not reach significance. This study suggests familial aggregation in the genetically isolated population. The high level of inbreeding makes this population valuable for finding novel genes involved in MS.

Introduction A genetic contribution to MS pathogenesis has been proven ever since the association with the HLA-DR2 locus was discovered more than 30 years ago. The search for additional MS risk genes has been frustrated by a significant lack of reproducibility. This was until recently. In the last two years there have been tremendous breakthroughs in the search for novel risk genes. The main reasons for this progress has been the introduction of novel techniques, improved statistical methods and an awareness that nothing can be solved without extensive international collaboration, including data from high numbers of patients. As anticipated the effects of these novel genes are small. In relation with the old stable giant of the associated HLA locus, the novel dwarfs have woken up, with odds ratios that generally are below 1.4. A. Current knowledge The genetic component in MS Although familial aggregation of MS has long been recognised, systematic ageadjusted recurrence risks for relatives of persons with MS were first published in 1988 (1). Subsequent studies showed that first-, second-and third-degree relatives of patients with MS were more likely to have the disease than the general population. Studies in twins showed a significant excess of concordance in monozygotic as compared to dizygotic twins (2-6). In a study of individuals with MS who were adopted an excess of risk in the genetically related family was found, whereas no excess of risk in the adopting family was found (7). Affected husband and wife couples do not occur more frequently than would be expected by chance. However the risk for their offspring is greater than if just one parent is affected (8). For halfsiblings the risk is approximately half the risk for full siblings, regardless whether they were raised together or apart (9, 10). Together these data suggest that living with someone who has MS only increases your risk on MS if you are a relative of that person, in which case your risk increases with relatedness. Mode of inheritance in MS Although, as discussed above, data confirm that genetic factors are unequivocally relevant in MS, most MS families contain no more than two or three affected individuals and no clear mode of inheritance can be inferred from segregation analysis. However the nonlinear relationship between familial recurrence risk and

Recent studies suggest that a history of cigarette smoking is a risk factor for multiple sclerosis (MS). We aimed to test the smoking effect in multiplex families, matching for both environmental and genetic factors. In a matched case-control study, 136 MS patients from 106 multiplex MS families were compared with their 204 healthy siblings as controls. Participants completed self-report questionnaires. Conditional logistic regression was used to analyse smoking and MS risk association while controlling for confounding by age and sex. Smoking history was classified in different variables. Within our survey the smoking history of MS patients and the controls did not differ. The odds of MS were comparable for different smoking levels. However, more intense exposure and women showed higher odds ratios, although non-significant. Association studies in families with relatively high genetic loading are unlikely to be confounded by smoking history.

Relapse rate is decreased during pregnancy in multiple sclerosis (MS). Risk for postpartum relapse is increased in the first 3 months after delivery. We aimed to study clinical course of MS around pregnancy, using clinical as well as self-report scales, including data on quality of life (QoL), and to identify clinical factors predisposing for postpartum relapse. We performed a prospective, longitudinal study among 35 MS patients and 20 controls. In patients we assessed expanded disability status scale (EDSS), the Guy’s neurological disability scale (GNDS) and the multiple sclerosis impact scale 29 (MSIS-29). In patients and controls we assessed the MOS 36 item short form health survey questionnaire (SF36), consisting of eight domains. The previously described surge in relapses after delivery was also obvious in this study (p = 0.005). At group level EDSS and MSIS-29 did not show overt fluctuations over time. The GNDS, however, improved during the third trimester, compared to the first trimester (p = 0.003). A concomitant improvement in the SF36 domains vitality (p < 0.001) and general health (p = 0.001) was found in patients. At the final visit, at least 9 months after delivery, no worsening of EDSS, GNDS, MSIS-29 or SF36 was observed compared with the (for MS, beneficial) third trimester. Duration of disease, relapses in the year preceding pregnancy or relapses during pregnancy were not associated with postpartum relapse. QoL is improved during pregnancy. Although relapse rate was increased directly after delivery, in the mid long term after delivery no adverse effects of pregnancy on MS were found.