A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility
Year: 2022
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Over 200 genetic loci have been associated with multiple sclerosis (MS) explaining ~ 50% of its heritability, suggesting that additional mechanisms may account for the "missing heritability" phenomenon. OBJECTIVE: To analyze a large cohort of Italian individuals to identify markers associated with MS with potential functional impact in the disease. METHODS: We studied 2571 MS and 3234 healthy controls (HC) of continental Italian origin. Discovery phase included a genome wide association study (1727 MS, 2258 HC), with SNPs selected according to their association in the Italian cohort only or in a meta-analysis of signals with a cohort of European ancestry (4088 MS, 7144 HC). Top associated loci were then tested in two Italian cohorts through array-based genotyping (903 MS, 884 HC) and pool-based target sequencing (588 MS, 408 HC). Finally, functional prioritization through conditional eQTL and mQTL has been performed. RESULTS: Top associated signals overlap with already known MS loci on chromosomes 3 and 17. Three SNPs (rs4267364, rs8070463, rs67919208), all involved in the regulation of TBKBP1, were prioritized to be functionally relevant. CONCLUSIONS: No evidence of novel signal of association with MS specific for the Italian continental population has been found; nevertheless, two MS loci seems to play a relevant role, raising the interest to further investigations for TBKBP1 gene.
Source: Journal of Neurology
Authors: Melissa Sorosina, Nadia Barizzone, Ferdinando Clarelli, Santosh Anand, Sara Lupoli, Erika Salvi, Eleonora Mangano, Roberta Bordoni, Tina Roostaei, Elisabetta Mascia, Miriam Zuccalà, Domizia Vecchio, Paola Cavalla, Silvia Santoro, Laura Ferrè, Alen Zollo, PROGEMUS, Lucia Florio, Paolo Ragonese, Alberto Gajofatto, Elio Scarpini, Domenico Caputo, Claudio Gasperini, Franco Granella, Paola Cavalla, Roberto Bergamaschi, Giovanni Ristori, Claudio Solaro, Filippo Martinelli Boneschi, Francesco Passantino, Maura Pugliatti, Antonio Gallo, Laura Brambilla, Marinella Clerico, Fioravante Capone, Maria Trojano, Cristina Barlassina, Daniele Cusi, Vittorio Martinelli, Giancarlo Comi, Maurizio Leone, Massimo Filippi, Nikolaos A. Patsopoulos, Philip L. De Jager, Gianluca De Bellis, Federica Esposito, Sandra D’Alfonso, Filippo Martinelli Boneschi
Institutions: IRCCS Ospedale San Raffaele, IRCCS San Raffaele Roma, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, University of Milano-Bicocca, University of Milan, Fondazione IRCCS Istituto Neurologico Carlo Besta, Institute of Biomedical Technologies, National Research Council, Columbia University Irving Medical Center, Azienda Ospedaliero Universitaria Maggiore della Carita, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Bio4Dreams (Italy), Casa Sollievo della Sofferenza, Broad Institute, Vita-Salute San Raffaele University, Massachusetts Institute of Technology, Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,990
OpenAlex ID: W4280558619