scholarly journals The genetic epidemiology of multiple sclerosis

1999 ◽  
Vol 354 (1390) ◽  
pp. 1623-1634 ◽  
Author(s):  
Alastair Compston
Keyword(s):  
Multiple Sclerosis ◽  
Complex Traits ◽  
Meta Analysis ◽  
Susceptibility Gene ◽  
Monozygotic Twins ◽  
Recurrence Risk ◽  
Disease Heterogeneity ◽  
Mediterranean Populations ◽  
Adjusted Risk ◽  
Sibling Pairs

Epidemiological studies have implicated an interplay between genetic and environmental factors in the aetiology of multiple sclerosis (MS). There is a familial recurrence rate of approximately 15%. Meta–analysis of the recurrence risk shows that the rate is highest overall for siblings, then parents and children, with lower rates in second– and third–degree relatives. Recurrence is highest for monozygotic twins. Conversely, the frequency in adoptees is similar to the population lifetime risk. The age–adjusted risk for half siblings is also less than for full siblings. Recurrence is higher in the children of conjugal pairs with MS than the offspring of single affecteds. These classical genetic observations suggest that MS is a complex trait in which susceptibility is determined by several genes acting independently or epistatically. Comparisons between co–affected sibling pairs provide no evidence for correlation with age or year at onset and mode of presentation or disability. Thus far, the identification of susceptibility genes has proved elusive but genetic strategies are now in place which should illuminate the problem. The main dividend will be an improved understanding of the pathogenesis. To date, population studies have demonstrated an association between the class II major histocompatibility complex (MHC) alleles DR15 and DQ6 and their corresponding genotypes. An association with DR4, with or without the primary DR15 link, is seen in some Mediterranean populations. Candidate gene approaches have otherwise proved unrewarding. Four groups of investigators have undertaken a systematic search of the genome. In common with most other complex traits, no major susceptibility gene has been identified but regions of interest have been provisionally identified. These genetic analyses are predicated on the assumption that MS is one disease. Genotypic and phenotypic analyses are beginning to question this assumption. A major part of future studies in the genetics of MS will be to resolve the question of disease heterogeneity.

Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals

1999 ◽  
Vol 5 (2) ◽  
pp. 74-77 ◽  
Author(s):  
Jennifer C Fulton ◽  
Robert I Grossman ◽  
Lois J Mannon ◽  
Jayaram Udupa ◽  
Dennis L Kolson
Keyword(s):  
Multiple Sclerosis ◽  
Monozygotic Twins ◽  
Subsequent Development ◽  
Monozygotic Twin ◽  
Lesion Volume ◽  
Sibling Pairs ◽  
Clinically Normal ◽  
Volumetric Assessment ◽  
Significant Difference ◽  
Normal Offspring

A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies of MS families, has been proposed for decades. Few reports provide detailed neurological as well as neuroradiological findings on these patients. We report total T2-weighted intracranial lesion volumes on members of three familial MS cohorts: a mother and father with conjugal MS with one affected son and a neurologically normal son and daughter, one pair of monozygotic twin sisters with MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings in a family with two affected parents and another affected child might demonstrate clinically silent T2-weighted lesions; and that monozygotic twins with MS are more likely to express similar T2-weighted lesion volumes than non-twin sibling pairs. We found clinically silent lesions in unaffected children of the symptomatic parent couple, with a significant difference in total T2 lesion volume between these unaffected siblings and their parents, as well as their affected brother. In our other sibling pairs, T2 lesion volumes were similar between the twins and significantly different in the non-twin pair, despite similar levels of clinical functioning as determined by EDSS scoring. These results suggest that foci of demyelination might be expected in clinically normal offspring of parents with MS, possibly reflecting a genetic predisposition to subsequent development of MS.

scholarly journals Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 87
Author(s):  
Sean M. Burnard ◽  
Rodney A. Lea ◽  
Miles Benton ◽  
David Eccles ◽  
Daniel W. Kennedy ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Complex Traits ◽  
Multiple Testing ◽  
Large Scale ◽  
Disease Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Elastic Net ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction

Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10−8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.

scholarly journals Epidemiology and genetics of hypodontia and microdontia: A study of twin families

2014 ◽  
Vol 85 (6) ◽  
pp. 980-985 ◽  
Author(s):  
Kwang Ho Jeong ◽  
Daeeun Kim ◽  
Yun-Mi Song ◽  
Joohon Sung ◽  
Young Ho Kim
Keyword(s):  
Environmental Factors ◽  
Monozygotic Twins ◽  
Genetic Effect ◽  
Recurrence Risk ◽  
Additive Genetic Effect ◽  
Dental Anomalies ◽  
Sibling Pairs ◽  
Recurrence Risk Ratio ◽  
Genetic And Environmental Factors ◽  
The Impact

ABSTRACT Objective:  To identify genetic and environmental factors contributing to hypodontia and microdontia by using Korean twin family data. Materials and Methods:  A total of 1267 individuals (525 men and 742 women; 180 monozygotic twins [MZ] and 43 dizygotic twins [DZ] from 282 families) underwent an oral examination as part of the Healthy Twin Study in Korea. Dental anomalies classified as hypodontia or microdontia were diagnosed using radiographs and clinical examinations. In order to estimate genetic contributions to dental anomalies, we estimated the pairwise concordance rate (PCR), recurrence risk ratio (RRR), and heritability (h2). Results:  The prevalence of hypodontia and microdontia was 3.55% and 3.00%, respectively. MZ had the highest PCR and RRR (13.0–15.3). The PCR and RRR values for both anomalies were much higher for DZ (5.0–11.9) than for siblings (1.4–2.6), despite the fact that DZ pairs and sibling pairs share 50% genetic identity. Further genetic analysis revealed both an additive genetic effect (0.38 when hypodontia and microdontia were pooled) and a strong “twin effect” (0.52 when hypodontia and microdontia were pooled). Conclusions:  This twin-based study revealed that the formation of dental anomalies is affected by both genetic and environmental factors, and that the impact of these factors varies according to the specific dental anomaly.

scholarly journals Statin use and clinical outcomes in patients with COVID-19: An updated systematic review and meta-analysis

2021 ◽  
pp. postgradmedj-2020-139172
Author(s):  
Rimesh Pal ◽  
Mainak Banerjee ◽  
Urmila Yadav ◽  
Sukrita Bhattacharjee
Keyword(s):  
Clinical Outcomes ◽  
Observational Studies ◽  
Fixed Effects ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Adverse Outcomes ◽  
Fixed Effects Model ◽  
Adjusted Risk ◽  
Risk Estimates ◽  
Statin Use

PurposeObservations studies have shown that prior use of statins is associated with a reduced risk of adverse clinical outcomes in patients with COVID-19. However, the available data are limited, inconsistent and conflicting. Besides, no randomised controlled trial exists in this regard. Hence, the present meta-analysis was conducted to provide an updated summary and collate the effect of statin use on clinical outcomes in COVID-19 using unadjusted and adjusted risk estimates.MethodsPubMed, Scopus and Web of Science databases were systematically searched using appropriate keywords till December 18 2020, to identify observational studies reporting clinical outcomes in COVID-19 patients using statins versus those not using statins. Prior and in-hospital use of statins were considered. Study quality was assessed using the Newcastle-Ottawa Scale. Unadjusted and adjusted pooled odds ratio (OR) with 95% CIs were calculated.ResultsWe included 14 observational studies pooling data retrieved from 19 988 patients with COVID-19. All the studies were of high/moderate quality. Pooled analysis of unadjusted data showed that statin use was not associated with improved clinical outcomes (OR 1.02; 95% CI 0.69 to 1.50, p=0.94, I2=94%, random-effects model). However, on pooling adjusted risk estimates, the use of statin was found to significantly reduce the risk of adverse outcomes (OR 0.51; 95% CI 0.41 to 0.63, p<0.0005, I2=0%, fixed-effects model).ConclusionsStatin use is associated with improved clinical outcomes in patients with COVID-19. Individuals with multiple comorbidities on statin therapy should be encouraged to continue the drug amid the ongoing pandemic.

scholarly journals Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ellen F. Mosleth ◽  
Christian Alexander Vedeler ◽  
Kristian Hovde Liland ◽  
Anette McLeod ◽  
Gerd Haga Bringeland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neural Development ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Retinol Binding Protein ◽  
Proteomics Data ◽  
Disease Heterogeneity ◽  
Low Levels

AbstractDespite intensive research, the aetiology of multiple sclerosis (MS) remains unknown. Cerebrospinal fluid proteomics has the potential to reveal mechanisms of MS pathogenesis, but analyses must account for disease heterogeneity. We previously reported explorative multivariate analysis by hierarchical clustering of proteomics data of MS patients and controls, which resulted in two groups of individuals. Grouping reflected increased levels of intrathecal inflammatory response proteins and decreased levels of proteins involved in neural development in one group relative to the other group. MS patients and controls were present in both groups. Here we reanalysed these data and we also reanalysed data from an independent cohort of patients diagnosed with clinically isolated syndrome (CIS), who have symptoms of MS without evidence of dissemination in space and/or time. Some, but not all, CIS patients had intrathecal inflammation. The analyses reported here identified a common protein signature of MS/CIS that was not linked to elevated intrathecal inflammation. The signature included low levels of complement proteins, semaphorin-7A, reelin, neural cell adhesion molecules, inter-alpha-trypsin inhibitor heavy chain H2, transforming growth factor beta 1, follistatin-related protein 1, malate dehydrogenase 1 cytoplasmic, plasma retinol-binding protein, biotinidase, and transferrin, all known to play roles in neural development. Low levels of these proteins suggest that MS/CIS patients suffer from abnormally low oxidative capacity that results in disrupted neural development from an early stage of the disease.

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