title: Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis.
abstract: BACKGROUND
  The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear.
  
  
  OBJECTIVE
  The objective of this paper is to identify genes, pathways and networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS).
  
  
  METHODS
  We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools.
  
  
  RESULTS
  No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: "oxidative phosphorylation" (FDRAAO=9*10(-4); FDRMSSS=3.0*10(-2)), "citrate (TCA) cycle" (FDRAAO=1.6*10(-2); FDRMSSS=3.2*10(-3)), and "B cell receptor signaling" (FDRAAO=3.1*10(-2); FDRMSSS=2.2*10(-3)). In addition, an enrichment of "chemokine signaling pathway" (FDR=9*10(-4)) for AAO and of "leukocyte transendothelial migration" (FDR=2.4*10(-3)) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively.
  
  
  CONCLUSIONS
  Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.
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: G
authors.initials: G
authors.lastname: Giacalone
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: A M
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: C
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: P
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: M
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/ Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Liberatore
authors.affiliation: Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Zauli
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: F
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rodegher
authors.affiliation: Department of Neurology, S. Antonio Abate Hospital, Gallarate, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ghezzi
authors.affiliation: Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Department DANA, G.F. Ingrassia, Neurosciences Section, Multiple Sclerosis Center, PO "G. Rodolico," Catania, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Patti
authors.affiliation: Department of Health Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Barizzone
authors.affiliation: Don C. Gnocchi Foundation ONLUS, IRCCS, 20100 Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Guerini
authors.affiliation: Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Department of Health Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy/ SCDU Neurologia, "A. Avogadro" University of Eastern Piedmont and AOU "Maggiore della Carità", Novara, Italy; IRCAD (Interdisciplinary Research Center of Autoimmune Diseases), "A. Avogadro" University of Piemonte Orientale, Novara, Italy.
authors.forename: M
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: G
authors.initials: G
authors.lastname: Comi
authors.affiliation: Department of Health Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy/ SCDU Neurologia, "A. Avogadro" University of Eastern Piedmont and AOU "Maggiore della Carità", Novara, Italy; IRCAD (Interdisciplinary Research Center of Autoimmune Diseases), "A. Avogadro" University of Piemonte Orientale, Novara, Italy.
authors.forename: S
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: F
authors.initials: F
authors.lastname: Martinelli Boneschi
mesh_terms: D000328:Adult; D017668:Age of Onset; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology; D012720:Severity of Illness Index
keywords: GWAS; age at onset; multiple sclerosis; network analysis; pathway analysis; primary-progressive; severity