Melissa Sorosina1, Paola Brambilla1, Ferdinando Clarelli1, Nadia Barizzone2, Sara Lupoli3, Clara Guaschino4, Ana Maria Osiceanu1, Lucia Moiola4, Angelo Ghezzi5, Gabriella Coniglio6, Francesco Patti7, Gianluigi Mancardi8, Paolo Manunta9, Nicola Glorioso10, Franca R Guerini11, Roberto Bergamaschi12, Franco Perla13, Vittorio Martinelli14, Daniele Cusi3, Maurizio Leone15, Giancarlo Comi4, Sandra D'Alfonso2, Filippo Martinelli-Boneschi16. 1. Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. 2. Interdisciplinary Research Center of Autoimmune Disease IRCAD, University of Eastern Piedmont, Italy Department of Health Sciences, University of Eastern Piedmont, Italy. 3. Department of Health Sciences, University of Milan and Genomics & Bioinformatics Unit, c/o Fondazione Filarete, Italy. 4. 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. 5. Department of Neurology, S. Antonio Abate Hospital, Italy. 6. Department of Neurology, Madonna delle Grazie Hospital, Italy. 7. Department DANA, G.F. Ingrassia, Neurosciences Section, Multiple Sclerosis Center, PO "G. Rodolico", Italy. 8. Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Italy. 9. Division of Nephrology and Dialysis, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Italy. 10. Hypertension and Related Diseases Centre-AOU, University of Sassari, Italy. 11. Don C. Gnocchi Foundation ONLUS, Italy. 12. Fondazione "Istituto Neurologico C. Mondino" IRCCS, Italy. 13. Department of Neurology, Mondovì Hospital, Italy. 14. Department of Neurology, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy. 15. Interdisciplinary Research Center of Autoimmune Disease IRCAD, University of Eastern Piedmont, Italy. 16. 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 contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
BACKGROUND: The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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: Emmanuelle Waubant; Robyn Lucas; Ellen Mowry; Jennifer Graves; Tomas Olsson; Lars Alfredsson; Annette Langer-Gould Journal: Ann Clin Transl Neurol Date: 2019-08-07 Impact factor: 4.511