title: The burden of multiple sclerosis variants in continental Italians and Sardinians.
abstract: BACKGROUND
  Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored.
  
  
  OBJECTIVE
  We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians.
  
  
  METHODS
  We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves.
  
  
  RESULTS
  As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles.
  
  
  CONCLUSIONS
  The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy/Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.affiliation: Centro di Ricerca, Sviluppo e Studi Superiori in Sardegna, Pula Cagliari, Italy/Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Zara
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Department of Health Sciences, University of Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lupoli
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy/Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Pitzalis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy/SC Neurologia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Leone
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy/Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Azienda Ospedaliera Brotzu, SC Neurologia e Stroke Unit, Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ferrigno
authors.affiliation: Don C Gnocchi Foundation IRCCS, Milan, Italy.
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brambilla
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Farina
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Murru
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Deidda
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy/Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Loi
authors.affiliation: Department of Health Sciences, University of Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barlassina
authors.affiliation: Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
authors.forename: Domizia
authors.initials: D
authors.lastname: Vecchio
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zauli
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Department of Health Sciences, University of Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Braga
authors.affiliation: Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Poddie
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy/Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cantello
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frau
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Lorefice
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Pugliatti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rosati
authors.affiliation: Azienda Ospedaliera Brotzu, SC Neurologia e Stroke Unit, Cagliari, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Melis
authors.affiliation: Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Marrosu
authors.affiliation: Department of Health Sciences, University of Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy/Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy/Department of Neurology, Division of Neuroscience, Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Cagliari, Italy serena.sanna@irgb.cnr.it sandra.dalfonso@med.unipmn.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
mesh_terms: D015415:Biomarkers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000208:ethnology; D009103:Multiple Sclerosis / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D015415:Biomarkers; D006680:HLA Antigens
keywords: Autoimmune disease; Italy; Mediterranean populations; Sardinia; epidemiology; genetic risk score; genetics; human leukocyte antigen; multiple sclerosis