TY - JOUR
T1 - A multi-step genomic approach prioritized TBKBP1 gene as relevant for multiple sclerosis susceptibility
AU - Sorosina, Melissa
AU - Barizzone, Nadia
AU - Clarelli, Ferdinando
AU - Anand, Santosh
AU - Lupoli, Sara
AU - Salvi, Erika
AU - Mangano, Eleonora
AU - Bordoni, Roberta
AU - Roostaei, Tina
AU - Mascia, Elisabetta
AU - Zuccalà, Miriam
AU - Vecchio, Domizia
AU - Cavalla, Paola
AU - Santoro, Silvia
AU - Ferrè, Laura
AU - Zollo, Alen
AU - Barlassina, Cristina
AU - Cusi, Daniele
AU - Martinelli, Vittorio
AU - Comi, Giancarlo
AU - Leone, Maurizio
AU - Filippi, Massimo
AU - Patsopoulos, Nikolaos A.
AU - De Jager, Philip L.
AU - De Bellis, Gianluca
AU - Esposito, Federica
AU - D’Alfonso, Sandra
AU - Martinelli Boneschi, Filippo
N1 - Publisher Copyright:
© The Author(s) 2022. corrected publication 2022.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Genetics
KW - Genome-wide association study
KW - Multiple sclerosis
KW - Susceptibility
KW - TBKBP1
UR - https://www.scopus.com/pages/publications/85134721164
U2 - 10.1007/s00415-022-11109-8
DO - 10.1007/s00415-022-11109-8
M3 - Article
SN - 0340-5354
VL - 269
SP - 4510
EP - 4522
JO - Journal of Neurology
JF - Journal of Neurology
IS - 8
ER -