G Giacalone1, F Clarelli2, A M Osiceanu2, C Guaschino1, P Brambilla2, M Sorosina2, G Liberatore1, A Zauli2, F Esposito1, M Rodegher3, A Ghezzi4, D Galimberti5, F Patti6, N Barizzone7, F Guerini8, V Martinelli3, M Leone9, G Comi1, S D'Alfonso9, F Martinelli Boneschi10. 1. 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. 2. Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. 3. Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. 4. Department of Neurology, S. Antonio Abate Hospital, Gallarate, Italy. 5. Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy. 6. Department DANA, G.F. Ingrassia, Neurosciences Section, Multiple Sclerosis Center, PO "G. Rodolico," Catania, Italy. 7. Department of Health Sciences, "A. Avogadro" University of Eastern Piedmont, Novara, Italy. 8. Don C. Gnocchi Foundation ONLUS, IRCCS, 20100 Milan, Italy. 9. 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. 10. 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.
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.
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: S Mahurkar; M Moldovan; V Suppiah; M Sorosina; F Clarelli; G Liberatore; S Malhotra; X Montalban; A Antigüedad; M Krupa; V G Jokubaitis; F C McKay; P N Gatt; M J Fabis-Pedrini; V Martinelli; G Comi; J Lechner-Scott; A G Kermode; M Slee; B V Taylor; K Vandenbroeck; M Comabella; F M Boneschi; C King Journal: Pharmacogenomics J Date: 2016-03-22 Impact factor: 3.550
Authors: Helen Tremlett; Feng Zhu; Douglas Arnold; Amit Bar-Or; Charles N Bernstein; Christine Bonner; Jessica D Forbes; Morag Graham; Janace Hart; Natalie C Knox; Ruth Ann Marrie; Ali I Mirza; Julia O'Mahony; Gary Van Domselaar; E Ann Yeh; Yinshan Zhao; Brenda Banwell; Emmanuelle Waubant Journal: Ann Clin Transl Neurol Date: 2021-12-09 Impact factor: 4.511