Genetic model of MS severity predicts future accumulation of disability.
Ann Hum Genet
; 84(1): 1-10, 2020 01.
Article
in En
| MEDLINE
| ID: mdl-31396954
ABSTRACT
No genetic modifiers of multiple sclerosis (MS) severity have been independently validated, leading to a lack of insight into genetic determinants of the rate of disability progression. We investigated genetic modifiers of MS severity in prospectively acquired training (N = 205) and validation (N = 94) cohorts, using the following advances (1) We focused on 113 genetic variants previously identified as related to MS severity; (2) We used a novel, sensitive outcome:
MS Disease Severity Scale (MS-DSS); (3) Instead of validating individual alleles, we used a machine learning technique (random forest) that captures linear and complex nonlinear effects between alleles to derive a single Genetic Model of MS Severity (GeM-MSS). The GeM-MSS consists of 19 variants located in vicinity of 12 genes implicated in regulating cytotoxicity of immune cells, complement activation, neuronal functions, and fibrosis. GeM-MSS correlates with MS-DSS (r = 0.214; p = 0.043) in a validation cohort that was not used in the modeling steps. The recognized biology identifies novel therapeutic targets for inhibiting MS disability progression.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biomarkers
/
Genetic Predisposition to Disease
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Polymorphism, Single Nucleotide
/
Intellectual Disability
/
Models, Genetic
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Multiple Sclerosis
Type of study:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Country/Region as subject:
America do norte
Language:
En
Journal:
Ann Hum Genet
Year:
2020
Type:
Article