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.

A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility

Pugliatti, M
Membro del Collaboration Group
2022

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.
2022
Sorosina, Melissa; Barizzone, Nadia; Clarelli, Ferdinando; Anand, Santosh; Lupoli, Sara; Salvi, Erika; Mangano, Eleonora; Bordoni, Roberta; Roostaei, Tina; Mascia, Elisabetta; Zuccalà, Miriam; Vecchio, Domizia; Cavalla, Paola; Santoro, Silvia; Ferrè, Laura; Zollo, Alen; Barlassina, Cristina; Cusi, Daniele; Martinelli, Vittorio; Comi, Giancarlo; Leone, Maurizio; Filippi, Massimo; Patsopoulos, Nikolaos A; De Jager, Philip L; De Bellis, Gianluca; Esposito, Federica; D'Alfonso, Sandra; Martinelli Boneschi, Filippo; Pugliatti, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2503587
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