Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer’s Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer’s disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7

BackgroundPrevious genetic and epidemiological studies have examined subpopulations from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) patient cohort, but an encompassing analysis of the study population has not yet been carried out.ObjectiveThis retrospective study examines patterns of multiple sclerosis (MS) prevalence in 13,663 cohort members, including 4,821 persons with MS or suspected MS and 8,842 family members.MethodsWe grouped participants into epidemiologic subgroups based on age of MS onset, clinical stage at diagnosis, symptom type at disease onset, sex, proband status, disability as measured by the EDSS, and ancestry based on reported ethnicity.ResultsWe observed a 2.7:1 MS prevalence ratio of women to men, though disease severity was greater for male patients. Variation in the age of disease onset between patients was only slightly associated with sex and strongly associated with disease type. Specific types of clinical symptoms at disease onset were associated with the prognosis. Regional residence did not correlate with disease onset, type, or severity.ConclusionPopulation trends, as presented here, are not explained by environmental factors alone, highlighting the need for a comprehensive genetic analysis to understand disease variance across families.

BackgroundAn increasing number of women with multiple sclerosis (wMS) are considering pregnancy. Prior studies suggest increased rate of elective cesarian sections (C-sections) in wMS.MethodsThe Canadian Multiple Sclerosis Pregnancy Study (CANPREG-MS) is a prospective study on pregnant wMS. This report shows comparisons between (i) CANPREG-MS wMS delivered by C-section and the general population and (ii) C-section and vaginal deliveries in this study cohort.ResultsCANPREG-MS has resulted in 170 deliveries with 63 by C-section. The proportion with C-sections in CANPREG-MS (37.1%) was significantly higher than that for the Canadian population (28%) ( p = .0085). The majority (66.7%) of C-sections were not planned, and typically were performed for obstetrical indications. C-sections were performed at an earlier gestational age than vaginal deliveries, although birthweight did not differ by mode of delivery in wMS. MS relapses (3.2%) and pseudo-relapses (3.2%) were rare in the first month after C-section deliveries, regardless of disease modifying therapy decisions during gestation and postpartum.ConclusionsC-sections were more common in wMS than the general population, but few were because of maternal MS. CANPREG-MS provides informative data for pregnancies in wMS with well-managed and relatively mild disease. This information is helpful to obstetrical and MS healthcare providers.

Background There is increasing need for evidence-based data on reproduction for women with multiple sclerosis (MS). First-trimester (first 13 weeks) miscarriages are relatively common in the general population. It is therefore important to have information on the frequency with which this occurs in women with MS. Methods The Canadian Multiple Sclerosis Pregnancy Study (CANPREG-MS) is a prospective study on women with MS who are pregnant or actively trying to conceive. As far as we are aware, this is the first study on miscarriages for this population that takes into account each woman’s entire pregnancy history (i.e. before and after the MS diagnosis as well as during enrollment in CANPREG-MS). Results There were 208 pregnancies during the study and 36 resulted in first-trimester miscarriage for a rate of 17.31%, within the expected range of 15%–20% for the general population. Conclusions CANPREG-MS provides real world data that there does not appear to be an increase in first-trimester miscarriages for women with MS. This information will be helpful to women with MS and their healthcare providers.

Background The effects of pregnancy on multiple sclerosis (MS) inflammatory activity are not well described in women with moderate to severe disabilities. Objective To quantify the peripartum annualized relapse rate (ARR) in women with MS with an Expanded Disability Status Scale (EDSS) ≥ 3. Methods We performed a retrospective cohort study of 85 pregnancies in 74 subjects with preconception EDSS ≥ 3. We quantified peripartum ARR and tested for risk factors predictive of peripartum relapses, postpartum brain magnetic resonance imaging activity (new T2 or gadolinium-enhancing lesions), and disability worsening. Results There were 74 live births, with a 56% operative delivery rate. In subjects with relapsing-remitting MS, ARR decreased to 0.11 during the third trimester of pregnancy compared to 0.59 in the year preconception and increased to 1.22 in the 3 months postpartum. Women with a higher preconception EDSS had higher odds of postpartum relapses and clinically significant worsening of disability as compared to subjects with a lower EDSS. Conclusions Moderately to severely disabled women with MS have a lower risk of relapse during pregnancy as compared to preconception, followed by a marked increase postpartum. Further studies are needed to identify ways to reduce peripartum inflammatory activity and disability progression in women with MS with moderate to severe disability.

Background: Peripartum depression (PPD) is underexplored in multiple sclerosis (MS). Objective: To evaluate prevalence of and risk factors for PPD in women with MS. Methods: Retrospective single-center analysis of women with MS with a live birth. Prevalence of PPD was estimated with logistic regression with generalized estimating equations (GEE). GEE evaluated predictors of PPD (e.g. age, marital status, parity, pre-pregnancy depression/anxiety, antidepressant discontinuation, sleep disturbance, breastfeeding, relapses, gadolinium-enhancing lesions, and disability). Factors significant in univariable analyses were included in multivariable analysis. Results: We identified 143 live births in 111 women (mean age 33.1 ± 4.7 years). PPD was found in 18/143 pregnancies (12.6%, 95% CI = 7.3–17.8). Factors associated with PPD included older age (OR 1.16, 95% CI = 1.03–1.32 for 1-year increase), primiparity (OR 4.02, CI = 1.14–14.23), pre-pregnancy depression (OR 3.70, CI = 1.27–10.01), sleep disturbance (OR 3.23, CI = 1.17–8.91), and breastfeeding difficulty (OR 3.58, CI = 1.27–10.08). Maternal age (OR 1.17, CI = 1.02–1.34), primiparity (OR 8.10, CI = 1.38–47.40), and pre-pregnancy depression (OR 3.89, CI = 1.04–14.60) remained significant in multivariable analyses. Relapses, MRI activity, and disability were not associated with PPD. Conclusion: The prevalence of PPD in MS appeared similar to the general population, but was likely underestimated due to lack of screening. PPD can affect MS self-management and offspring development, and prospective studies are needed.

OBJECTIVE:To evaluate the impact of temporal increase of female to male (F:M) sex ratio for persons with multiple sclerosis (MS) on the familial risk (empiric recurrence risks or RRs) for biological relatives of affected individuals.METHODS:Detailed family histories were systematically obtained from people with MS attending the University of British Columbia Hospital MS Clinic. The study cohort was born in 1970 or more recently. Data were collected from 1 September 2015 to 31 January 2019. The study was designed to allow only one proband per family. Age-corrected RRs for biological relatives of probands were calculated based on a modification of the maximum-likelihood approach.RESULTS:Data analyses were possible for 746 unique probands (531 females; 215 males) and 19,585 of their biological relatives. RRs were temporally impacted.CONCLUSION:Both genetic sharing and environmental factors are important in determining RRs. It appears that there is an increase in MS risk due to environmental factors in later life (i.e. not shared family environment). Environmental exposures in genetically predisposed individuals might be driving the MS risk. The increase in F:M ratio of RRs for sisters/brothers of female probands over time is likely due to environmental differences.

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.

Objective The objective of this prospective "real world" study is to gain insight into the different "roads to conception" that women with MS take as part of the prospective Canadian Multiple Sclerosis Pregnancy Study (CANPREG-MS). Methods Participants are women with MS who are planning a pregnancy. Data cut-off for analyses was April 30, 2020. Results We believe this is the first prospective National study of women with MS planning pregnancies. The data are for the first 44 women enrolled of whom 26 achieved pregnancy by cut-off date. Seven women used assisted reproductive technologies (ARTs); 6 stopped disease modifying therapy (DMT) against their neurologists' recommendations; 6 had an interruption(s) in trying to conceive due to MS relapses, MRI-detected inflammation, or limited "windows of opportunity" between DMT courses. Conclusion The study illustrates the roads that women take to conception, even if they are on the same therapy and have similar clinical expression of MS. Advice given by treating neurologists on washout periods show discrepancies. This paper highlights the real problem that there is no definitive, international consensus on managing these women due to the lack of "real world" data and thus the goal of CANPREG-MS is to provide such real world data.

Genetic and functional analyses of the inflammasome suggest a role for this multiprotein complex in the biological mechanisms leading to the onset and progression of multiple sclerosis (MS). Nucleotide-binding, leucine-rich repeat (NLR) receptors trigger the activation and assembly of specific inflammasomes in response to danger signals. Mining exome sequencing data from 326 MS patients identified 17 rare missense or nonsense variants in NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLRP7 and NLR family CARD domain containing 4 (NLRC4). Genotyping these variants in 2503 MS cases and 1076 healthy controls did not result in statistically significant differences between groups, and segregation analysis within MS families was largely unsupportive of co-segregation of these variants with disease. However, the identification of MS patients harboring rare homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile), a variant in NLRP3 (p.Leu832Ile) resulting in the substitution of a critical amino acid for the formation of its leucine-rich repeat domain, and several MS patients with NLRC4 variants (p.Arg310Ter and p.Glu600Ter) causing protein truncations suggest that rare protein-altering variants in inflammasome-activating NLR receptors may contribute to MS risk.

Purpose: : To what extent depression may negatively impact successful aging with multiple sclerosis (MS) is not known. We examined the impact of depression/depressive symptoms on lifestyle choices (diet, exercise, smoking and alcohol), participation and health-related quality of life (HRQoL) among older people living with MS (n = 742). Methods: : Based on self-reported depression diagnosis and scores on the Hospital Anxiety and Depression Scale, we divided the sample into four groups: 1. No depression diagnosis and low symptoms (n = 412), 2. Diagnosed with depression and low symptoms (n = 103), 3. Diagnosed with depression and high symptoms (n = 87), and 4. No depression diagnosis and high symptoms (n = 140). We used regression modelling to predict outcomes, controlling for age, MS disease duration, type of MS at initial diagnosis and disability. Results: : A high proportion (44.5%) reported either being diagnosed with depression, having high levels of symptoms or both. Only 12.1% reported that they were prescribed anti-depressants and 13.6% utilized psychosocial services. Compared to those with depression who had low symptoms, respondents who had high depressive symptoms (n = 227) were more likely to be non-exercisers (OR 1.85, 95%CI 1.02-3.34, p = 0.042), consume a poor diet (OR 2.12, 95%CI 1.27-3.52, p = 0.004), have the lowest levels of participation (OR 3.36, 95%CI 1.74-6.49, p = 0.0003) and report the poorest HRQoL (OR 1.95, 95%CI 1.17-3.26, p = 0.011). Men and people experiencing higher levels of disability and fatigue were at greater risk of having high symptoms and being undiagnosed. Conclusion: : Undiagnosed and under-treated depression is common among older people living with MS and adversely impacts health choices.

Background: Multiple sclerosis (MS) is the most common cause of neurological disability, other than trauma, among young adults of reproductive age. In contrast to the past, today there is very little lag time from clinical onset to diagnosis. Disease-modifying therapies are also now available outside of clinical trials. However, there is very little evidence-based population data to help an individual with MS make informed decisions with respect to reproductive options. Objective: The objective of this study is to develop a Canada-wide, prospective population-based registry of women with MS who are either trying to become pregnant and/or have become pregnant. Methods: The study represents a "real-world" scenario. Women with MS are invited to participate, regardless of clinical course, therapy, disease duration, and/or disability. The methodology to develop such a registry is very complex making it imperative to understand the design and rationale when interpreting results for clinical purposes. Results: This paper is a comprehensive discussion of the study rationale and methodology. Conclusions: The study is ongoing, with over 100 potential participants. Numerous future publications are envisioned as the study progresses. The present paper is thus designed to be the key referral paper for subsequent publications in which it will not be possible to provide the necessary detailed information on rationale and methodology.

The relative roles of genes and environment (not intra-familial environment) and interactions thereof continue to confound better understanding of the pathogenesis of multiple sclerosis (MS) and can also impact recurrence risks for family members as well as genetic family studies. Strong evidence for non-familial environmental factors is suggested by the change in the sex ratio (female:male) of MS patients over the last four decades.

Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-located innate immune sensor that inhibits major pro-inflammatory pathways such as type I interferon and nuclear factor-κB signaling. We generated a novel, spontaneous, and rapidly progressing mouse model of multiple sclerosis (MS) by crossing myelin-specific T-cell receptor (TCR) transgenic mice with Nlrx1-/- mice. About half of the resulting progeny developed spontaneous experimental autoimmune encephalomyelitis (spEAE), which was associated with severe demyelination and inflammation in the central nervous system (CNS). Using lymphocyte-deficient mice and a series of adoptive transfer experiments, we demonstrate that genetic susceptibility to EAE lies within the innate immune compartment. We show that NLRX1 inhibits the subclinical stages of microglial activation and prevents the generation of neurotoxic astrocytes that induce neuronal and oligodendrocyte death in vitro. Moreover, we discovered several mutations within NLRX1 that run in MS-affected families. In summary, our findings highlight the importance of NLRX1 in controlling the early stages of CNS inflammation and preventing the onset of spontaneous autoimmunity.

RÉSUMÉLes facteurs de protection retrouvés chez des octogénaires atteints de sclérose en plaques (SP) vivant à domicile ont été comparés à ceux d’individus sans SP du même groupe d’âge et de personnes moins âgées atteintes de SP. Les données provenant des octogénaires atteints de SP (n = 23) et d’un groupe de répondants plus jeunes avec cette maladie (n = 61) ont été tirées d’une enquête canadienne sur le vieillissement avec SP. Les données des groupes avec SP ont été comparées aux statistiques nationales d’octogénaires de la population générale. Les octogénaires avec SP présentaient plus d’incapacités et une prévalence plus élevée de troubles de l’humeur, mais étaient physiquement plus actifs que la population d’octogénaires de l’enquête canadienne. Les octogénaires avec SP ont déclaré éprouver moins de stress et de fatigue que le groupe d’individus plus jeunes avec SP. Bien que la différence d’âge entre les deux groupes avec SP soit d’une dizaine d’années, ces groupes ont rapporté des niveaux similaires de soutien social, d’aisance financière, d’incapacité physique et de participation. Le maintien d’appuis solides (sociaux et financiers), d’une attitude positive, la pratique d’activité physique et la participation aux activités quotidiennes peuvent contribuer au vieillissement dans la collectivité chez les individus avec SP, malgré les défis amenés par cette maladie.

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