scholarly journals A higher burden of multiple sclerosis genetic risk confers an earlier onset

2021 ◽  
pp. 135245852110531
Author(s):  
Elina Misicka ◽  
Mary F Davis ◽  
Woori Kim ◽  
Steven W Brugger ◽  
Jeremy Beales ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Disease Duration ◽  
Age Of Onset ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Histocompatibility Complex ◽  
Risk Variants ◽  
The Mean ◽  
Strong Inverse Relationship

Background: Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration. Objectives: Determine the influence of MS genetic predisposition on age of onset. Methods: We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of HLA-DRB1*15:01 alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex. Results: The mean age at onset was 32 years, 29% were male, and 46% were HLA-DRB1*15:01 carriers. For those with the greatest genetic risk burden (the highest GRS quintile with two HLA-DRB1*15:01 alleles) were on average 5 years younger at onset ( p = 0.002) than those with the lowest genetic risk burden (the lowest GRS quintile with no HLA-DRB1*15:01 alleles). There was a strong inverse relationship between the MS genetic risk burden and age at onset of MS ( p < 5 × 10−8). Conclusion: We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease.

scholarly journals A higher burden of multiple sclerosis genetic risk confers an earlier onset

2020 ◽  
Author(s):  
Elina Misicka ◽  
Mary F. Davis ◽  
Woori Kim ◽  
Steven W. Brugger ◽  
Jeremy Beales ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Association Analysis ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Genome Wide Association ◽  
Multiple Sclerosis Risk ◽  
Risk Variants ◽  
Genome Wide

AbstractMultiple sclerosis is a neurodegenerative, autoimmune disease characterized by inrreversible neurological disability. The age at onset of multiple sclerosis is an objective and influential predictor of the evolution of multiple sclerosis independent of disease duration. Little is known about the mechanisms contributing to variation in onset age of multiple sclerosis, though HLA-DRB1*15:01, the predominant risk variant, confers an earlier onset. Here we present an age at onset genome-wide association analysis for 9.2 million variants, including gene-based and pathway enrichment analyses, for 3,495 cases who were non-Latinx white with onset ≥18 years. We investigated whether a higher burden of multiple sclerosis risk variants conferred an earlier age at onset for combinations of HLA-DRB1*15:01 alleles and quintiles of a genetic risk score for 200 risk variants that reside outside the major histocompatibility complex. The study population had a mean age at onset of 32 years, 29% was male, and 46% were HLA-DRB1*15:01 carriers. HLA-DRB1*15:01 carriers were on average one year younger at onset than non-carriers (p<0.001); a similar effect was observed for a 10-risk-allele increase in the genetic risk score (p<1×10-8). Those in the highest genetic risk score quintile (n=717) were on average 2.5 years younger at onset than those in the lowest quintile (n=698; p=1.2×10-7). For those with the greatest genetic risk burden (highest genetic risk score quintile with two HLA-DRB1*15:01 alleles) were on average five years younger at onset (p=0.002) than those with the lowest genetic risk burden (lowest genetic risk score quintile with no HLA-DRB1*15:01 alleles). There was an apparent inverse relationship between the genetic multiple sclerosis risk burden and age at onset of multiple sclerosis (p<5×10-8). We did not observe any individual variants reaching genome-wide significance in the genome-wide association analysis of age at onset. The most significantly associated independent genic loci (p<5×10-6) were located within HLA-DQB1, COL21A1, LINC01484, UBR3, and CSMD1. At the gene-level, the most significant associations (p<5×10-5) were for SSB, TRAFD1, HECTD2, MMP8, NAA25 and UBR3. There was an enrichment of genes involved in adaptive and innate immunity, specifically genes in the complement pathway, and genes involved in synapses and collagen biosynthesis. In summary, we demonstrated a significant gradient between elevated genetic risk burden and an earlier onset of multiple sclerosis.

scholarly journals Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

2013 ◽  
Vol 20 (6) ◽  
pp. 660-668 ◽  
Author(s):  
Hanne F Harbo ◽  
Noriko Isobe ◽  
Pål Berg-Hansen ◽  
Steffan D Bos ◽  
Stacy J Caillier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Human Leukocyte ◽  
Oligoclonal Bands ◽  
Nucleotide Polymorphisms ◽  
Risk Variants ◽  
The Impact ◽  
Genetic Risk Variants

Background: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. Objective: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. Methods: Norwegian MS patients ( n = 639) and healthy controls ( n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients ( n = 1997) and controls ( n = 708). Results: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts ( P << 10−22). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. Conclusion: The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

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

2014 ◽  
Vol 21 (11) ◽  
pp. 1463-1467 ◽  
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.

scholarly journals Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 234-248 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Xylena Reed ◽  
Lynne Krohn ◽  
Karl Heilbron ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Lewy Body ◽  
Disease Risk ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Lewy Body Dementia ◽  
Risk Variants ◽  
Genome Wide

Abstract Parkinson’s disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson’s disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson’s disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to &gt;10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson’s disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson’s disease cases, 13 431 Parkinson’s disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson’s disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson’s disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson’s disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson’s disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

scholarly journals Genetic risk factors for pediatric-onset multiple sclerosis

2017 ◽  
Vol 24 (14) ◽  
pp. 1825-1834 ◽  
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.

scholarly journals Burden of risk variants correlates with phenotype of multiple sclerosis

2015 ◽  
Vol 21 (13) ◽  
pp. 1670-1680 ◽  
Author(s):  
Kelly Hilven ◽  
Nikolaos A Patsopoulos ◽  
Bénédicte Dubois ◽  
An Goris
Keyword(s):  
Multiple Sclerosis ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Disease Onset ◽  
Human Leukocyte ◽  
Female Gender ◽  
Oligoclonal Bands ◽  
Risk Variants ◽  
Parametric Analyses

Background: More than 100 common variants underlying multiple sclerosis (MS) susceptibility have been identified, but their effect on disease phenotype is still largely unknown. Objective: The objective of this paper is to assess whether the cumulative genetic risk score of currently known susceptibility variants affects clinical presentation. Methods: A cumulative genetic risk score was based on four human leukocyte antigen (HLA) and 106 non-HLA risk loci genotyped or imputed in 842 Belgian MS patients and 321 controls. Non-parametric analyses were applied. Results: An increased genetic risk is observed for MS patients, including subsets such as oligoclonal band-negative and primary progressive MS patients, compared to controls. Within the patient group, a stronger association between HLA risk variants and the presence of oligoclonal bands, an increased immunoglobulin G (IgG) index and female gender was apparent. Results suggest an association between a higher accumulation of non-HLA risk variants and increased relapse rate as well as shorter relapse-free intervals after disease onset. Conclusion: MS patients display a significantly increased genetic risk compared to controls, irrespective of disease course or presence of oligoclonal bands. Whereas the cumulative burden of non-HLA risk variants appears to be reflected in the relapses of MS patients, the HLA region influences intrathecal IgG levels.

Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis

2000 ◽  
Vol 6 (1) ◽  
pp. 32-36 ◽  
Author(s):  
S JM Weatherby ◽  
C LA Mann ◽  
M B Davies ◽  
D Carthy ◽  
A A Fryer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Apolipoprotein E ◽  
Disease Duration ◽  
Age Of Onset ◽  
Neurological Diseases ◽  
Age At Onset ◽  
Apoe Genotype ◽  
Disease Process ◽  
Genotype Frequencies ◽  
Significant Difference

Allelic variants of the apolipoprotein E (APOE) gene influence the course of several neurological diseases. In multiple sclerosis the concentration of APOE in cerebrospinal fluid and its intrathecal synthesis is reduced. Specific isoforms of APOE may also be important and it has been suggested that possession of the e4 allele may be associated with a more aggressive disease process. These data prompted us to re-examine, in a large group of patients with multiple sclerosis, the proposal that allelism in the apolipoprotein gene influences disease course. Genotypes were determined in a well-defined group of 370 unrelated Caucasians with clinically definite multiple sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded. Disability was measured using the Kurtzke expanded disability status score in patients with a disease duration of 10 years or greater. There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders. APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found. This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of multiple sclerosis.

scholarly journals Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia

2019 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Xylena Reed ◽  
Lynne Krohn ◽  
Karl Heilbron ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Cathepsin B ◽  
Lewy Body ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Lewy Body Dementia ◽  
Genome Wide Association ◽  
Risk Variants ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.Using multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.

scholarly journals Patients with neuromyelitis optica have a more severe disease than patients with relapsingremitting multiple sclerosis, including higher risk of dying of a demyelinating disease

2013 ◽  
Vol 71 (5) ◽  
pp. 275-279 ◽  
Author(s):  
Denis Bernardi Bichuetti ◽  
Enedina Maria Lobato de Oliveira ◽  
Nilton Amorin de Souza ◽  
Mar Tintoré ◽  
Alberto Alain Gabbai
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Disease Duration ◽  
Demyelinating Disease ◽  
Age Of Onset ◽  
Severe Disease ◽  
Expanded Disability Status Scale ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis

Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done.Methods:Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007.Results:Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p≪0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15.Conclusion:Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease.

Early and Late Onset Bipolar Disorders in Older Adults

2017 ◽  
Vol 41 (S1) ◽  
pp. S211-S211
Author(s):  
N. Smaoui ◽  
L. Zouari ◽  
N. Charfi ◽  
M. Maâlej-Bouali ◽  
N. Zouari ◽  
...  
Keyword(s):  
Older Adults ◽  
Bipolar Disorder ◽  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Bipolar Disorders ◽  
Medical Diagnoses ◽  
The Mean ◽  
Bipolar Patients

IntroductionAge of onset of illness may be useful in explaining the heterogeneity among older bipolar patients.ObjectiveTo examine the relationship of age of onset with clinical, demographic and behavioral variables, in older patients with bipolar disorder.MethodsThis was a cross-sectional, descriptive and analytical study, including 24 patients suffering from bipolar disorders, aged 65 years or more and followed-up in outpatient psychiatry unit at Hedi Chaker university hospital in Sfax in Tunisia. We used a standardized questionnaire including socio-demographic, behavioral and clinical data. Age of onset was split at age 40 years into early-onset (< 40 years; n = 12) and late-onset (≥ 40 years; n = 12) groups.ResultsThe mean age for the entire sample was 68.95 years. The mean age of onset was 39.95 years. The majority (60%) of patients were diagnosed with bipolar I. Few meaningful differences emerged between early-onset and late-onset groups, except that tobacco use was significantly higher in the late-onset group (66.6% vs. 16.6%; P = 0.027). No significant differences between the early-onset and late-onset groups were seen on demographic variables, family history and number of medical diagnoses or presence of psychotic features.ConclusionOur study found few meaningful behavioral differences between early versus late age at onset in older adults with bipolar disorder.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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