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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00415-022-11109-8.