title: Genetic burden of common variants in progressive and bout-onset multiple sclerosis.
abstract: The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear.
  
  
  
  The aim of the study is to evaluate and compare the proportion of liability explained by common SNPs and the genetic burden of MS-associated SNPs in progressive onset (PrMS) and bout-onset (BOMS) cases.
  
  
  
  We estimated the proportion of variance in disease liability explained by 296,391 autosomal SNPs in cohorts of Italian PrMS and BOMS patients using the genome-wide complex trait analysis (GCTA) tool, and we calculated a weighted genetic risk score (wGRS) based on the known MS-associated loci.
  
  
  
  Our results identified that common SNPs explain a greater proportion of phenotypic variance in BOMS (36.5%±10.1%) than PrMS (20.8%±6.0%) cases, and a trend of decrease was observed when testing primary progressive (PPMS) without brain MRI inflammatory activity (p = 7.9 × 10(-3)). Similarly, the wGRS and the variance explained by MS-associated SNPs were higher in BOMS than PPMS in males (wGRS: 6.63 vs 6.51, p = 0.04; explained variance: 4.8%±1.5% vs 1.7%±0.6%; p = 0.05).
  
  
  
  Our results suggest that the liability of disease is better captured by common genetic variants in BOMS than PrMS cases. The absence of inflammatory activity and male gender further raise the difference between clinical courses.
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brambilla
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Interdisciplinary Research Center of Autoimmune Disease IRCAD, University of Eastern Piedmont, Italy Department of Health Sciences, University of Eastern Piedmont, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Barizzone
authors.affiliation: Department of Health Sciences, University of Milan and Genomics & Bioinformatics Unit, c/o Fondazione Filarete, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lupoli
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Guaschino
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Osiceanu
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Moiola
authors.affiliation: Department of Neurology, S. Antonio Abate Hospital, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ghezzi
authors.affiliation: Department of Neurology, Madonna delle Grazie Hospital, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coniglio
authors.affiliation: Department DANA, G.F. Ingrassia, Neurosciences Section, Multiple Sclerosis Center, PO "G. Rodolico", Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Patti
authors.affiliation: Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mancardi
authors.affiliation: Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.affiliation: Hypertension and Related Diseases Centre-AOU, University of Sassari, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.affiliation: Don C. Gnocchi Foundation ONLUS, Italy.
authors.forename: Franca R
authors.initials: FR
authors.lastname: Guerini
authors.affiliation: Fondazione "Istituto Neurologico C. Mondino" IRCCS, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bergamaschi
authors.affiliation: Department of Neurology, Mondovì Hospital, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Perla
authors.affiliation: Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Department of Health Sciences, University of Milan and Genomics & Bioinformatics Unit, c/o Fondazione Filarete, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Interdisciplinary Research Center of Autoimmune Disease IRCAD, University of Eastern Piedmont, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Leone
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Interdisciplinary Research Center of Autoimmune Disease IRCAD, University of Eastern Piedmont, Italy Department of Health Sciences, University of Eastern Piedmont, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy martinelli.filippo@hsr.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D055815:Young Adult
chemical_list: D005819:Genetic Markers
keywords: Multiple sclerosis; genome-wide association study; heritability; primary progressive; relapsing–remitting