title: Genetic burden in multiple sclerosis families.
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.
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Isobe
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.|UPMC-INSERM-CNRS-ICM, UMR 975-7225, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Damotte
authors.affiliation: Department of Clinical Neurosciences, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK.
authors.forename: V Lo
authors.initials: VL
authors.lastname: Re
authors.affiliation: Department of Clinical Neurosciences, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ban
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Pappas
authors.affiliation: UPMC-INSERM-CNRS-ICM, UMR 975-7225, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Guillot-Noel
authors.affiliation: UPMC-INSERM-CNRS-ICM, UMR 975-7225, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Rebeix
authors.affiliation: Department of Clinical Neurosciences, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Compston
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Mack
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Cozen
authors.affiliation: UPMC-INSERM-CNRS-ICM, UMR 975-7225, Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Oksenberg
authors.affiliation: Department of Clinical Neurosciences, Addenbrooke's, Hospital, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: P-A
authors.initials: PA
authors.lastname: Gourraud
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D040741:Genetic Load; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
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