Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis

Abstract

Objective: 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. Methods: 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. Results: 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. Interpretation: 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.

Association of Vitamin D Polygenic Risk Scores and Disease Outcome in People With Multiple Sclerosis

“…Limited studies have examined disease heterogeneity in MS using PGS. In a study by Vandebergh et al, 58 the “response to vitamin D” pathway was identified by Gene Ontology as affecting susceptibility to relapses. In a more recent study, 25(OH)D-related genetic variants were identified by GWAS (using similar studies as in the current report) and 2 sample Mendelian Randomization (MR) was applied to link 25(OH)D with relapse risk in a cohort of 506 PwMS.…”

“…Although we restricted to individuals with European ancestry, its possible different distributions of underlying contributors to vitamin D status (e.g., obesity) could contribute. We also did not have relapse (the primary outcome in Vandebergh et al 58 ) in all cohorts, although relapse in our study was derived using a rigorously collected clinical trial cohort. Notably, we also did not apply an identical set of methods in that we considered 25(OH)D PGS instead of MR in our primary analysis; the PGS approach is expected to be more powerful (although has a higher probability of false positives).…”

Effects of Vitamin D and Body Mass Index on Disease Risk and Relapse Hazard in Multiple Sclerosis

“…In our previous GWAS, we have demonstrated that genetic associations with relapse hazard are enriched for genes in the response to vitamin D gene ontology set by performing a competitive gene-set enrichment analysis. 19 In addition, studies applying a polygenic score approach have shown an association between increased 25OHD levels and a decreased relapse hazard in MS. 38,39 These studies differ from our 2-sample MR design by combining multiple genetic variants into a single variable, i.e., polygenic score, and/or by not limiting to genome-wide significant SNVs. Moreover, tools for pleiotropy and heterogeneity assessment are limited in the polygenic score setting.…”

“…Progress in availability of genome-wide association studies (GWASs) for heterogeneity measures, such as relapse hazard in MS, 19 enables us to apply the Mendelian randomization framework (MR) for causal inference assessments with heterogeneity measures as outcome. In this way, MR is an elegant tool to inform intervention strategies, also after disease onset, when the patient is followed up by the neurologist.…”

Towards a global view of multiple sclerosis genetics

“…Gene-gene interactions also occur at this locus in populations of European ancestryseveral alleles modulate the effect of HLA-DRB1*15:01 8,41 . There is little evidence to suggest that the MHC influences MS phenotypes (for example, relapse rate, severity or relapsing-remitting versus progressive disease) besides age of onset in European populations [41][42][43] .The frequency, distribution and haplotypes of HLA alleles differ between ancestral populations (Figure 1) 44,45 . Some alleles are absent in the European population so their influence on MS risk cannot be studied in populations of European ancestry.…”