Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis.

Marijne Vandebergh, Till F M Andlauer, Yuan Zhou, Klara Mallants, Friederike Held, Lilian Aly, Bruce V Taylor, Bernhard Hemmer, Bénédicte Dubois, An Goris

Annals of neurology 2021 May

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Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date. We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis. The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10-10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10-6 ). The MS genetic risk scores, however, were not associated with relapse hazard. Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity. ANN NEUROL 2021;89:884-894. © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Citation

Marijne Vandebergh, Till F M Andlauer, Yuan Zhou, Klara Mallants, Friederike Held, Lilian Aly, Bruce V Taylor, Bernhard Hemmer, Bénédicte Dubois, An Goris. Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis. Annals of neurology. 2021 May;89(5):884-894