Abstract
A previous study using cumulative genetic risk estimations in multiple sclerosis (MS) successfully tracked the aggregation of susceptibility variants in multi-case and single-case families. It used a limited description of susceptibility loci available at the time (17 loci). Even though the full roster of MS risk genes remains unavailable, we estimated the genetic burden in MS families and assess its disease predictive power using up to 64 single-nucleotide polymorphism (SNP) markers according to the most recent literature. A total of 708 controls, 3251 MS patients and their relatives, as well as 117 twin pairs were genotyped. We validated the increased aggregation of genetic burden in multi-case compared with single-case families (P=4.14e−03) and confirm that these data offer little opportunity to accurately predict MS, even within sibships (area under receiver operating characteristic (AUROC)=0.59 (0.55, 0.53)). Our results also suggest that the primary progressive and relapsing-type forms of MS share a common genetic architecture (P=0.368; difference being limited to that corresponding to ±2 typical MS-associated SNPs). We have confirmed the properties of individual genetic risk score in MS. Comparing with previous reference point for MS genetics (17 SNPs), we underlined the corrective consequences of the integration of the new findings from GWAS and meta-analysis.
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Acknowledgements
This study was supported by the National Institutes of Health (grant RO1NS26799 RO1NS19142), the National Multiple Sclerosis Society (grant RG2901) and the Cambridge NIHR Biomedical Research Centre, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Fondation d’Aide pour la Recherche sur la Sclérose En Plaques (ARSEP), the Association Française contre les Myopathies (AFM) and GIS-IBISA. The research leading to these results has received funding from the program ‘Investissements d’avenir’ ANR-10-IAIHU-06. We acknowledge use of the cohort of the REFGENSEP and thank ICM, CIC Pitié-Salpêtrière, Généthon and REFGENSEP’s members for their help and support. NI is a postdoctoral fellow supported by Japan Society for Promotion of Science. VD received a travel grant from ARSEP. P-AG is a recipient of the Nancy Davis Foundation young investigator award. We acknowledge the assistance of Stacy Caillier, Adam Santaniello, Vinod Bakthavachalam Jinyang Wang and Matthew Chan in sample and data management.
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Isobe, N., Damotte, V., Lo Re, V. et al. Genetic burden in multiple sclerosis families. Genes Immun 14, 434–440 (2013). https://doi.org/10.1038/gene.2013.37
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DOI: https://doi.org/10.1038/gene.2013.37
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