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Background: Inter-individual differences in treatment response are marked in multiple sclerosis (MS). This is true for Natalizumab (NTZ), to which a subset of patients displays sub-optimal treatment response. We conducted a multi-centric genome-wide association study (GWAS), with additional pathway and network analysis to identify genetic predictors of response to NTZ., Methods: MS patients from three different centers were included. Response to NTZ was dichotomized, nominating responders (R) relapse-free patients and non-responders (NR) all the others, over a follow-up of 4 years. Association analysis on ~ 4.7 M imputed autosomal common single-nucleotide polymorphisms (SNPs) was performed fitting logistic regression models, adjusted for baseline covariates, followed by meta-analysis at SNP and gene level. Finally, these signals were projected onto STRING interactome, to elicit modules and hub genes linked to response., Results: Overall, 1834 patients were included: 119 from Italy (R = 94, NR = 25), 81 from Germany (R = 61, NR = 20), and 1634 from Sweden (R = 1349, NR = 285). The top-associated variant was rs11132400 T (p = 1.33 × 10 -6 , OR = 0.58), affecting expression of several genes in the locus, like KLKB1. The interactome analysis implicated a module of 135 genes, with over-representation of terms like canonical WNT signaling pathway (p adjust  = 7.08 × 10 -6 ). Response-associated genes like GRB2 and LRP6, already implicated in MS pathogenesis, were topologically prioritized within the module., Conclusion: This GWAS, the largest pharmacogenomic study of response to NTZ, suggested MS-implicated genes and Wnt/β-catenin signaling pathway, an essential component for blood-brain barrier formation and maintenance, to be related to treatment response., Competing Interests: Declarations Competing interests F. Clarelli, A. Corona, K. Pääkkönen, M. Sorosina, A. Zollo, F. Piehl, T. Olsson, P. Stridh, M. Jagodic, B. Hemmer, C. Gasperi, A. Harroud, K. Shchetynsky, A. Mingione, E. Mascia, K. Misra, A. Giordano, M.L. Terzi Mazzieri, A. Priori, J. Saarela, I. Kockum, M. Filippi, F. Esposito, and F. Martinelli Boneschi have no competing interests to declare that are relevant to the topic of the present study. T. Olsson has received honoraria from Biogen, Merck, Novartis, and Sanofi for lectures/advisory Boards, and unrestricted MS research grants from the same companies. B. Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon, and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. He is associated with DIFUTURE (Data Integration for Future Medicine) [BMBF 01ZZ1804[A-I]]. C. Gasperi received funding from the German Federal Ministry of Education and Research (BMBF—161L0216), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—GA 2913/3–1, project number 513308106), and the Hertie Foundation (P1200018). A. Harroud has received consultancy fees from Biogen and Pfizer, and received compensation for serving on a scientific advisor board for Amgen. A. Priori is the founder and the chair of the scientific advisory board of Newronika SpA, Milan Italy. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Associate Editor of Radiology, and Associate Editor of Neurological Sciences. He received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme, and he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). F. Esposito received consulting and speaking fees from Novartis and Sanofi Genzyme. F. Martinelli Boneschi has received compensation for consulting services and/or speaking activities from Teva Pharmaceutical Industries, Sanofi Genzyme, Merck-Serono, Biogen Idec, Roche, Medday, and Excemed, and received research support from Merck, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and Fondazione Cariplo., (© 2024. The Author(s).)