Genetic Risk Burden in Familial Multiple Sclerosis: Insights from a Dutch Cohort Study
Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative disease in which both genetic susceptibility and environmental exposures contribute to disease risk. A longstanding observation in MS epidemiology is that a substantial proportion of patients report affected relatives, suggesting familial aggregation and an inherited component of susceptibility. In this 2016 study by Mescheriakova and colleagues, the authors addressed a central question in MS genetics: whether patients from Dutch multiplex MS families (families with multiple affected members) carry a greater burden of known common MS risk variants than sporadic MS cases. The work is particularly important because previous studies had reported inconsistent findings, and because a clearer understanding of genetic burden in familial MS could improve etiological models of disease and guide future genetic study design.
Study Design, Cohorts, and Clinical Characterization
The investigators analyzed three groups from the Netherlands: 283 sporadic MS cases, 169 probands from multiplex MS families (selected from 286 familial cases for comparative analyses), and 2028 healthy controls from the Rotterdam Study. All participants underwent genotyping after quality control procedures, and only individuals of European descent were retained for analysis. The authors also collected a robust set of clinical variables, including sex, age at disease onset, disease duration, MS course, Expanded Disability Status Scale (EDSS), and Multiple Sclerosis Severity Score (MSSS). Notably, the familial and sporadic MS groups did not differ significantly in key clinical characteristics, which strengthens the interpretation that subsequent differences in genetic burden are less likely to reflect major baseline clinical imbalances.
Genetic Risk Scoring Strategy and Analytical Framework
To quantify cumulative inherited susceptibility, the authors calculated a weighted genetic risk score (wGRS) using 102 non-HLA MS risk loci derived from previously established genome-wide association findings, and they also modeled the additional contribution of the major risk allele HLA-DRB11501. This distinction is scientifically meaningful because the HLA region, especially HLA-DRB11501, has the strongest known common genetic effect in MS and can dominate risk models if not analyzed separately. Receiver operating characteristic (ROC) analyses and area under the curve (AUC) statistics were then used to test how well different genetic models discriminated cases from controls and familial from sporadic MS. The study therefore combined genetic epidemiology with translational prediction modeling, rather than limiting itself to allele-frequency comparisons alone.
Principal Finding: Familial MS Carries a Higher Common-Variant Burden
The central result is that the weighted genetic risk score including both non-HLA loci and HLA-DRB11501 was significantly higher in familial MS than in sporadic MS, and both patient groups had higher scores than healthy controls. By contrast, when only the 102 non-HLA loci were used, the familial-versus-sporadic comparison showed only a trend and did not reach statistical significance. This pattern strongly indicates that the observed excess genetic burden in multiplex families is driven predominantly by the HLA component. Consistent with this interpretation, the frequency of the HLA-DRB11501 risk allele was substantially higher in familial MS than in sporadic MS and controls, supporting the conclusion that familial clustering in this cohort is enriched for the strongest currently known common MS susceptibility signal.
Clinical Correlates: Age at Onset but Limited Association with Severity
The authors also explored whether a higher genetic burden translated into a distinct clinical phenotype. They observed that a higher wGRS (particularly when HLA-DRB1*1501 was included) was associated with a lower age at disease onset when all MS cases were analyzed together, and this association was significant in sporadic MS cases. However, the same relationship was not detected in familial cases analyzed separately, likely reflecting limited statistical power in that subgroup, as the authors discuss. Importantly, the study found no meaningful association between genetic risk score and disease severity (MSSS), disability level (EDSS), sex differences, or major disease course categories (such as relapsing-remitting versus progressive forms). These findings reinforce a recurrent theme in MS genetics: common susceptibility variants are more informative for disease risk than for downstream disease progression or severity.
Predictive Performance and Clinical Utility of the Genetic Models
A particularly valuable aspect of this paper is its sober evaluation of prediction performance. Although adding HLA-DRB1*1501 to the non-HLA risk loci improved discrimination, the overall predictive capacity remained modest. The combined model achieved better AUC values for distinguishing familial MS from controls than sporadic MS from controls, reflecting the higher genetic loading in multiplex families, but the authors emphasize that this performance is still inadequate for clinical decision-making in a relatively rare disease such as MS. Furthermore, attempts to distinguish familial from sporadic MS using these genetic scores produced low AUCs, indicating poor practical utility. The paper therefore makes an important translational point: statistically significant genetic enrichment does not automatically translate into clinically useful prediction tools.
Scientific Implications, Limitations, and Future Directions
Mescheriakova et al. conclude that Dutch multiplex MS families are more heavily loaded with common MS risk variants than sporadic cases, with the difference largely attributable to HLA-DRB11501. At the same time, they carefully acknowledge limitations, including moderate sample size, potential underpowering for some subgroup analyses, reliance on a tagging SNP to represent HLA-DRB11501, and the use of effect sizes derived from broader MS populations rather than familial-specific cohorts. The authors’ forward-looking perspective remains highly relevant: understanding familial MS aggregation will likely require integration of common variants, rare variants, and environmental exposures, rather than common-risk SNPs alone. As a scientific contribution, this study is significant not because it provides a ready-to-use predictive test, but because it clarifies the genetic architecture of familial MS and helps define the next methodological steps for more comprehensive risk modeling.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Mescheriakova, J. Y., Broer, L., Wahedi, S., Uitterlinden, A. G., van Duijn, C. M., & Hintzen, R. Q. (2016). Burden of genetic risk variants in multiple sclerosis families in the Netherlands. Multiple Sclerosis Journal–Experimental, Translational and Clinical, 2, 2055217316648721.
