Pregnancy does not modify the risk of MS in genetically susceptible women

ObjectiveTo use the case-only gene-environment (G E) interaction study design to estimate interaction between pregnancy before onset of MS symptoms and established genetic risk factors for MS among White adult females.MethodsWe studied 2,497 female MS cases from 4 cohorts in the United States, Sweden, and Norway with clinical, reproductive, and genetic data. Pregnancy exposure was defined in 2 ways: (1) live birth pregnancy before onset of MS symptoms and (2) parity before onset of MS symptoms. We estimated interaction between pregnancy exposure and established genetic risk variants, including a weighted genetic risk score and both HLA and non-HLA variants, using logistic regression and proportional odds regression within each cohort. Within-cohort associations were combined using inverse variance meta-analyses with random effects. The case-only G × E independence assumption was tested in 7,067 individuals without MS.ResultsEvidence for interaction between pregnancy exposure and established genetic risk variants, including the strongly associated HLA-DRB1*15:01 allele and a weighted genetic risk score, was not observed. Results from sensitivity analyses were consistent with observed results.ConclusionOur findings indicate that pregnancy before symptom onset does not modify the risk of MS in genetically susceptible White females.

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Genetic risk factors for pediatric-onset multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517733551 ◽

2017 ◽

Vol 24 (14) ◽

pp. 1825-1834 ◽

Cited By ~ 15

Author(s):

Milena A Gianfrancesco ◽

Pernilla Stridh ◽

Xiaorong Shao ◽

Brooke Rhead ◽

Jennifer S Graves ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Risk ◽

Genetic Risk Score ◽

The United States ◽

Individual Risk ◽

Class Iii ◽

Risk Variants ◽

Weighted Genetic Risk Score ◽

Meta Analyses ◽

Pediatric Onset

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years ( n = 569) and controls ( n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

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Susceptibility to childhood onset rheumatoid arthritis: investigation of a weighted genetic risk score that integrates cumulative effects of five genetic risk variants

Pediatric Rheumatology ◽

10.1186/1546-0096-10-s1-a116 ◽

2012 ◽

Vol 10 (S1) ◽

Author(s):

Sampath Prahalad ◽

Milton Brown ◽

Susan D Thompson ◽

Michael Zwick ◽

David Cutler ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Cumulative Effects ◽

Childhood Onset ◽

Risk Variants ◽

Weighted Genetic Risk Score ◽

Genetic Risk Variants

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Comparison of methods to construct a genetic risk score for prediction of rheumatoid arthritis in the population-based Nord-Trøndelag Health Study, Norway

Rheumatology ◽

10.1093/rheumatology/kez638 ◽

2020 ◽

Vol 59 (7) ◽

pp. 1743-1751 ◽

Cited By ~ 1

Author(s):

S Rostami ◽

M Hoff ◽

M A Brown ◽

K Hveem ◽

V Videm

Keyword(s):

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Selection Criterion ◽

Predictive Ability ◽

Population Based ◽

Sensitivity Analyses ◽

Risk Scores ◽

Predictive Values ◽

Weighted Genetic Risk Score

Abstract Objectives To evaluate selection methods among published single-nucleotide polymorphisms (SNPs) associated with RA to construct predictive genetic risk scores (GRSs) in a population-based setting. Methods The Nord-Trøndelag Health (HUNT) Study is a prospective cohort study among the whole adult population of northern Trøndelag, Norway. Participants in HUNT2 (1995–1997) and HUNT3 (2006–2008) were included (489 RA cases, 61 584 controls). The initial SNP selection from relevant genome-wide studies included 269 SNPs from 30 studies. Following different selection criteria, SNPs were weighted by published odds ratios. The sum of each person’s carriage of all weighted susceptibility variants was calculated for each GRS. Results The best-fitting risk score included 27 SNPs [weighted genetic risk score 27 (wGRS27)] and was identified using P-value selection criterion ≤5 × 10−8, the largest possible SNP selection without high linkage disequilibrium (r2 < 0.8), and lasso regression to select for positive coefficients. In a logistic regression model adjusted for gender, age and ever smoking, wGRS27 was associated with RA [odds ratio 1.86 (95% CI 1.71, 2.04) for each s.d. increase, P < 0.001]. The AUC was 0.76 (95% CI 0.74, 0.78). The positive and negative predictive values were 1.6% and 99.7%, respectively, and the positive predictive value was not improved in sensitivity analyses subselecting participants to illustrate settings with increased RA prevalences. Other schemes selected more SNPs but resulted in GRSs with lower predictive ability. Conclusion Constructing a wGRS based on a smaller selection of informative SNPs improved predictive ability. Even with a relatively high AUC, the low PPV illustrates that there was a large overlap in risk variants among RA patients and controls, precluding clinical usefulness.

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Inverse correlation of genetic risk score with age at onset in bout-onset and progressive-onset multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514561910 ◽

2014 ◽

Vol 21 (11) ◽

pp. 1463-1467 ◽

Cited By ~ 7

Author(s):

Melissa Sorosina ◽

Federica Esposito ◽

Clara Guaschino ◽

Ferdinando Clarelli ◽

Nadia Barizzone ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Age At Onset ◽

Inverse Correlation ◽

Inflammatory Phase ◽

Risk Variants ◽

Weighted Genetic Risk Score

We correlated the weighted genetic risk score measured using 107 established susceptibility variants for multiple sclerosis (MS) with the age at onset in bout-onset (BOMS, n=906) and progressive-onset MS Italian patients (PrMS) ( n=544). We observed an opposite relationship in the two disease courses: a higher weighted genetic risk score was associated with an earlier age at onset in BOMS (rho= −0.1; p=5 × 10−3) and a later age at onset in PrMS cases (rho=0.07; p=0.15) ( p of difference of regression=1.4 × 10−2). These findings suggest that established MS risk variants anticipate the onset of the inflammatory phase, while they have no impact on, or even delay, the onset of the progressive phase.

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A Weighted Genetic Risk Score Predicts Surgical Recurrence Independent of High-Risk Clinical Features in Dupuytren’s Disease

Plastic & Reconstructive Surgery ◽

10.1097/prs.0000000000005208 ◽

2019 ◽

Vol 143 (2) ◽

pp. 512-518 ◽

Cited By ~ 3

Author(s):

Sophie A. Riesmeijer ◽

Oliver W. G. Manley ◽

Michael Ng ◽

Ilja M. Nolte ◽

Dieuwke C. Broekstra ◽

...

Keyword(s):

High Risk ◽

Clinical Features ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Dupuytren’S Disease ◽

Dupuytren's Disease ◽

Surgical Recurrence ◽

Weighted Genetic Risk Score

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Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity

Addiction Biology ◽

10.1111/adb.12741 ◽

2019 ◽

Vol 25 (1) ◽

Cited By ~ 3

Author(s):

Ahmed El‐Boraie ◽

Taraneh Taghavi ◽

Meghan J. Chenoweth ◽

Koya Fukunaga ◽

Taisei Mushiroda ◽

...

Keyword(s):

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Weighted Genetic Risk Score

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Genetic Risk Score of 46 Type 2 Diabetes Risk Variants Associates With Changes in Plasma Glucose and Estimates of Pancreatic -Cell Function Over 5 Years of Follow-Up

Diabetes ◽

10.2337/db13-0362 ◽

2013 ◽

Vol 62 (10) ◽

pp. 3610-3617 ◽

Cited By ~ 28

Author(s):

E. A. Andersson ◽

K. H. Allin ◽

C. H. Sandholt ◽

A. Borglykke ◽

C. J. Lau ◽

...

Keyword(s):

Type 2 Diabetes ◽

Risk Score ◽

Plasma Glucose ◽

Genetic Risk ◽

Cell Function ◽

Genetic Risk Score ◽

Pancreatic Cell ◽

Risk Variants

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Faculty Opinions recommendation of Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1587956.1078054 ◽

2010 ◽

Author(s):

Sreeram Ramagopalan ◽

Lahiru Handunnetthi

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Genetic Risk Factors ◽

Clinical Algorithm ◽

Multiple Sclerosis Susceptibility ◽

Weighted Genetic Risk Score

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Burden of genetic risk variants in multiple sclerosis families in the Netherlands

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217316648721 ◽

2016 ◽

Vol 2 ◽

pp. 205521731664872 ◽

Cited By ~ 2

Author(s):

Julia Y Mescheriakova ◽

Linda Broer ◽

Simin Wahedi ◽

André G Uitterlinden ◽

Cornelia M van Duijn ◽

...

Keyword(s):

Multiple Sclerosis ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Weighted Genetic Risk Score ◽

Sporadic Cases ◽

Multiplex Families ◽

The Difference ◽

Multiple Sclerosis Patients ◽

Genetic Burden

Background Approximately 20% of multiple sclerosis patients have a family history of multiple sclerosis. Studies of multiple sclerosis aggregation in families are inconclusive. Objective To investigate the genetic burden based on currently discovered genetic variants for multiple sclerosis risk in patients from Dutch multiple sclerosis multiplex families versus sporadic multiple sclerosis cases, and to study its influence on clinical phenotype and disease prediction. Methods Our study population consisted of 283 sporadic multiple sclerosis cases, 169 probands from multiplex families and 2028 controls. A weighted genetic risk score based on 102 non-human leukocyte antigen loci and HLA-DRB1*1501 was calculated. Results The weighted genetic risk score based on all loci was significantly higher in familial than in sporadic cases. The HLA-DRB1*1501 contributed significantly to the difference in genetic burden between the groups. A high weighted genetic risk score was significantly associated with a low age of disease onset in all multiple sclerosis patients, but not in the familial cases separately. The genetic risk score was significantly but modestly better in discriminating familial versus sporadic multiple sclerosis from controls. Conclusion Familial multiple sclerosis patients are more loaded with the common genetic variants than sporadic cases. The difference is mainly driven by HLA-DRB1*1501. The predictive capacity of genetic loci is poor and unlikely to be useful in clinical settings.

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