Huge international studies including >40,000 people with MS have helped to untangle how genes affect your risk of developing MS. Attempts to work out how genes affect the course of the disease once it’s established have been far less successful. This is probably because the disease’s natural course is so radically altered by disease-modifying therapies. Understanding how genes influence disease severity requires finding large numbers of untreated people, which is difficult (for good reasons). Hopefully there should not be anyone out there who is not offered treatment promptly after getting a diagnosis, and so doing this kind of study well takes a lot of hard work.
A new study from the MS genetics group in Leuwen set out to tackle this problem and have done a great job. They asked whether they could find genetic variants that explained why some people have higher relapse rates than others. They recruited 506 people with relapsing MS who were not on treatment during the study period. They directly measured genetic variation at >700,000 sites in the genome. Using a statistical method called imputation – essentially a ‘filling in the gaps’ method – they expanded their results to include variation at >7 million sites. They tested each of these 7 million variants for their association with how long it took each person to have their next relapse.
In total there were 1412 relapses in the study. There was no strong association between overall genetic risk for developing MS and the number of relapses. 10 sites in the genome were associated with relapse risk. These variants suggested that vitamin D signalling may be an important determinant of relapse risk. One of these signals – the variant rs11871306 – was also associated in an independent cohort. Each extra copy of the ‘risk’ variant was associated with ~2x the risk of relapse over any given time period. The variant sits within a gene called WNT9B, and probably affects how expression of this gene is regulated.
This study is (I think) only the second to show an association between a genetic variant and relapse rate in MS. Although it is very interesting and impressive, we must be careful not to overstate the role of this variant. The variant they detected was associated with a a big difference in the time to the next relapse (1 year vs 2.2 years), but importantly it is only carried by ~4% of people from European ancestry. It is therefore unlikely to explain a large amount of person-to-person variation in relapse rate. Further work is going to be needed to understand how this variant might impact on MS biology. Ultimately, to really understand the genetics of relapses far bigger sample sizes are going to be needed.
A key point here is that the authors found no link between genes for MS susceptibility and relapse rate. If this is true, it’s a very important finding suggesting that the pathways that ‘light the fire’ to cause MS in the first place are distinct from the pathways that perpetuate and aggravate the disease.
Are we any closer to using genetics in the clinic to predict how the disease would behave if left untreated? No, is the short answer. Much bigger studies are needed to understand how much of disease severity is genetic and what genes drive it. It is likely to be a long time (I would guess >10 years) before genetics can add anything meaningful to predicting an individual’s disease course on top of metrics we use already like MRI activity. Nevertheless, we have to start somewhere and this study has made some important headway in an important area for our basic understanding of MS biology.
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 genome-wide association study (GWAS) in a discovery cohort and investigated the genome-wide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2231 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.