title: Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction.
abstract: OBJECTIVE
  To investigate the role of known multiple sclerosis (MS)-associated genetic variants in MS familial aggregation, clinical expression, and accuracy of disease prediction in sporadic and familial cases.
  
  
  METHODS
  A total of 1,443 consecutive patients were screened for MS and familial autoimmune history in a hospital-based Italian cohort. Among them, 461 sporadic and 93 familial probands were genotyped for 107 MS-associated polymorphisms. Their effect sizes were combined to calculate the weighted genetic risk score (wGRS).
  
  
  RESULTS
  Family history of MS was reported by 17.2% of probands, and 33.8% reported a familial autoimmune disorder, with autoimmune thyroiditis and psoriasis being the most frequent. No difference in wGRS was observed between sporadic and familial MS cases. In contrast, a lower wGRS was observed in probands with greater familial aggregation (>1 first-degree relative or >2 relatives with MS) (p = 0.03). Also, female probands of familial cases with greater familial aggregation had a lower wGRS than sporadic cases (p = 0.0009) and male probands of familial cases (p = 0.04). An inverse correlation between wGRS and age at onset was observed (p = 0.05). The predictive performance of the genetic model including all known MS variants was modest but greater in sporadic vs familial cases (area under the curve = 0.63 and 0.57).
  
  
  CONCLUSIONS
  Additional variants outside the known MS-associated loci, rare variants, and/or environmental factors may explain disease occurrence within families; in females, hormonal and epigenetic factors probably have a predominant role in explaining familial aggregation. The inclusion of these additional factors in future versions of aggregated genetic measures could improve their predictive ability.
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Guaschino
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferre'
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mascia
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Santoro
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pagnesi
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Radaelli
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Colombo
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Moiola
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Mariaemma
authors.initials: M
authors.lastname: Rodegher
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Department of Neurology (F.E., C.G., L.F., M.P., M. Radaelli, B.C., L.M., M. Rodegher, V.M., G.C., F.M.B.) and Laboratory of Genetics of Neurological Complex Disorders (F.E., C.G., M.S., F.C., L.F., E.M., S.S., M.P., G.C., F.M.B.), Institute of Experimental Neurology, Division of Neuroscience, and Center for Translational Genomics and Bioinformatics (E.S.), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi