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Background and purpose: In a longitudinal population-based dataset of patients with multiple sclerosis (MS), we have previously observed a substantial increase in the female to male sex ratio in Canada over the last 50 years. Here, we aimed to determine whether this change in sex ratio is related to the clinical course of MS. Methods: We calculated sex ratios by birth year in 11 868 patients with relapsing–remitting (RR) MS and 2825 patients with primary progressive (PP) MS identified as part of the Canadian Collaborative Project on the Genetic Susceptibility to MS. Results: Year of birth was a significant predictor for sex ratio in RR MS ( P < 0.0001, χ2 = 21.2; Spearman’s rank correlation r = 0.67), but not for PP MS ( P = 0.44, χ2 = 0.6; Spearman’s rank correlation r = 0.11). Conclusions: An increase in the number of female RR MS patients over time accounts for the increasing sex ratio of MS. This has implications for pathogenesis, for assessment of clinical trial results and for disease prevention. The factors underlying the selective increase in MS in females need to be uncovered. [ABSTRACT FROM AUTHOR]

Size and ascertainment constraints often limit twin studies to concordance comparisons between identical and fraternal twins. Here we report the final results of a longitudinal, population-based study of twins with multiple sclerosis (MS) in Canada. Bias was demonstrably minimized, and an estimated 75% of all Canadian MS twin pairs were ascertained, giving a sample sufficiently large (n = 370) to permit additional informative comparisons. Twinning was not found to affect prevalence, and twins with MS did not differ from nontwins for DR15 allele frequency nor for MS risk to their siblings. Probandwise concordance rates of 25.3% (SE ñ 4.4) for monozygotic (MZ), 5.4% (±2.8) for dizygotic (DZ), and 2.9% (±0.6) for their nontwin siblings were found. MZ twin concordance was in excess of DZ twin concordance. The excess concordance in MZ was derived primarily from like-sexed female pairs with a probandwise concordance rate of 34 of 100 (34 ñ 5.7%) compared with 3 of 79 (3.8 ± 2.8%) for female DZ pairs. We did not demonstrate an MZ/DZ difference in males, although the sample size was small. We observed a 2-fold increase in risk to DZ twins over nontwin siblings of twins, but the difference was not significant. [ABSTRACT FROM AUTHOR]

Reports implicating specific transmissible agents in multiple sclerosis (MS) susceptibility continue to appear. We therefore re-evaluated MS risk in 687 stepsiblings of 19 746 MS index cases. We found the risk of MS to be indistinguishable from that of the general population after diagnostic verification. These results are coherent with studies of adopted children, half siblings and conjugals, showing no risk attributable to the familial microenvironment. This family based genetic epidemiological approach found no trace of transmissibility other than genetic from one affected individual to another in the high prevalence area of Canada. This adds to existing data showing that the action of environment in influencing MS risk is operative at a population level. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20--50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% ( 2 test, p=0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal halfsiblings (15 of 1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility. [ABSTRACT FROM AUTHOR]

Inherited monogenic disease has an enormous impact on the well-being of children and their families. Over half of the children living with one of these conditions are without a molecular diagnosis because of the rarity of the disease, the marked clinical heterogeneity, and the reality that there are thousands of rare diseases for which causative mutations have yet to be identified. It is in this context that in 2010 a Canadian consortium was formed to rapidly identify mutations causing a wide spectrum of pediatric-onset rare diseases by using whole-exome sequencing. The FORGE (Finding of Rare Disease Genes) Canada Consortium brought together clinicians and scientists from 21 genetics centers and three science and technology innovation centers from across Canada. From nation-wide requests for proposals, 264 disorders were selected for study from the 371 submitted; disease-causing variants (including in 67 genes not previously associated with human disease; 41 of these have been genetically or functionally validated, and 26 are currently under study) were identified for 146 disorders over a 2-year period. Here, we present our experience with four strategies employed for gene discovery and discuss FORGE's impact in a number of realms, from clinical diagnostics to the broadening of the phenotypic spectrum of many diseases to the biological insight gained into both disease states and normal human development. Lastly, on the basis of this experience, we discuss the way forward for rare-disease genetic discovery both in Canada and internationally., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Ataxia demonstrates substantial phenotypic and genetic heterogeneity. We set out to determine the diagnostic yield of exome sequencing in pediatric patients with ataxia without a molecular diagnosis after standard-of-care assessment in Canada. FORGE (Finding Of Rare disease GEnes) Canada is a nation-wide project focused on identifying novel disease genes for rare pediatric diseases using whole-exome sequencing. We retrospectively selected all FORGE Canada projects that included cerebellar ataxia as a feature. We identified 28 such families and a molecular diagnosis was made in 13; a success rate of 46%. In 11 families, we identified mutations in genes associated with known neurological syndromes and in two we identified novel disease genes. Exome analysis of sib pairs and/or patients born to consanguineous parents was more likely to be successful (9/13) than simplex cases (4/15). Our data suggest that exome sequencing is an effective first line test for pediatric patients with ataxia where a specific single gene is not immediately suspected to be causative., (© 2013 WILEY PERIODICALS, INC.)

Background: The ratio of female to male (F:M) multiple sclerosis (MS) cases varies geographically, generally being greater in areas of high prevalence. In many regions, including Canada, rising MS incidence in women has been implied by the marked increase in F:M ratio., Methods: We examined the F:M ratio over time in MS patients in the Canadian Collaborative Study born outside Canada, with onset postmigration (n = 2531). We compared the trends to native-born Canadians, by region of origin and age at migration., Results: Regression analysis showed that year of birth (YOB) was a significant predictor of sex ratio in immigrants (chi(2) = 21.4, p<0.001 correlation r = 0.61). The rate of change in sex ratio was increasing in all migrant subgroups (by a factor of 1.16 per 10-year period, p<0.001), with the steepest increase observed in those from Southern Europe (1.27/10 years, p<0.001). The overall immigrant F:M ratio was 2.17, but varied by country of origin. It was significantly lower in migrants from Southern Europe compared with Northern Europe or USA (1.89 vs 2.14 and 2.86, p = 0.023 and p = 0.0003, respectively). Increasing age at immigration was associated with decreasing sex ratio (p = 0.041). The sex ratio of individuals migrating <21 was significantly higher than those migrating > or =21 (2.79 vs 1.96, p = 0.004)., Conclusions: MS sex ratio in immigrants to Canada is increasing but variable by region of origin and influenced by age at migration. The findings highlight the importance of environmental effect(s) in MS risk, which are likely gender-specific.

Background: Multiple sclerosis (MS) is a complex neurologic disease with a striking geographical distribution. In Canada, prevalence is high in Caucasians of Northern European ancestry and uncommon in North American Aboriginals, many of whom now have Caucasian admixture., Methods: The population-based Canadian Collaborative Project on the Genetic Susceptibility to MS provided the characteristics of 58 individuals with 1 Caucasian and 1 North American Aboriginal parent from a database of 30,000 MS index cases., Results: We found that MS index cases with a Caucasian mother and a North American Aboriginal father had a higher sib recurrence risk and greater F:M sex ratio (p = 0.043) than patients with a North American Aboriginal mother and Caucasian father., Conclusions: Maternal parent-of-origin effects in multiple sclerosis disease etiology previously seen in studies of half-siblings and avuncular pairs are also seen in Caucasian-North American Aboriginal admixture matings and warrant further investigation. A differential influence of maternal risk transmission on the sex ratio of affected offspring is implied. The method of analysis used may have broader implications for detection of parent-of-origin effects in admixture cohorts.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

The objective of this study was to investigate genes involved in the metabolism and function of vitamin D as candidate genes for genetic susceptibility to MS. Restriction fragment length polymorphisms and highly polymorphic microsatellite markers within or very close to the 1,25(OH)2D3 receptor (VDR) [12q14], the vitamin D binding protein (DBP) [4q12], and the 25(OH)D2 1alpha-hydroxylase [12q13] loci were analyzed for linkage or association with MS. We found no evidence for linkage or association of these candidate genes with MS in the Canadian population.

BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.