A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC

Progressive supranuclear palsy (PSP) is a rare 4-repeat tauopathy that causes behavioural, movement and cognitive abnormalities. We genotyped all available clinical and histopathological PSP cases in Spain and Portugal (N = 522), and conducted the largest PSP GWAS of the Iberian population to date....

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Detalhes bibliográficos
Autores: García-González, P; Lara, HR; Compta, Y; Fernandez, M; van der Lee, SJ; de Rojas, I; Saiz, L; Painous, C; Camara, A; Muñoz, E; Marti, MJ; Valldeoriola, F; Puerta, R; Illán-Gala, I; Pagonabarraga, J; Dols-Icardo, O; Kulisevsky, J; Fortea, J; Lleó, A; Olivé, C; de Boer, SCM; Hulsman, M; Pijnenburg, YAL; Belloso, RD; Muñoz-Delgado, L; Rueda, DB; Gómez-Garre, P; Aldecoa, I; Aragonés, G; Vara, JH; Mendioroz, M; Pérez-Tur, J; Visser, PJ; den Braber, A; Papma, JM; Montes, AM; Rodriguez-Rodriguez, E; Blázquez-Folch, J; Miguel, A; García-Gutiérrez, F; Cano, A; Valero, S; Marquié, M; Capdevila-Bayo, M; Rosende-Roca, M; Quintela, I; Carracedo, A; Tàrraga, L; Real, LM; Royo, JL; Erro, ME; Guerrero, C; Torres, DC; Blázquez-Estrada, M; San Millán, B; Teijeira, S; Rolan, DV; Hernández, I; Sánchez-Soblechero, A; de la Casa-Fages, B; López, SS; Baviera-Muñoz, R; Lavín, A; Taipa, R; Amer, G; Martinez-Saez, E; Fernández-Matarrubia, M; Lage-Martínez, C; Alvarez, V; Molina-Porcel, L; Holstege, H; Mir, P; Belbin, O; Boada, M; Fernández, V; Bullido, MJ; Rábano, A; Sánchez-Juan, P; Ruiz, A
Tipo de documento: Artigo
Estado:Published version
Data de publicação:2025
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p19933
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19933
Nível de acesso:Acesso aberto
Descrição
Resumo:Progressive supranuclear palsy (PSP) is a rare 4-repeat tauopathy that causes behavioural, movement and cognitive abnormalities. We genotyped all available clinical and histopathological PSP cases in Spain and Portugal (N = 522), and conducted the largest PSP GWAS of the Iberian population to date. Genetic burden analysis revealed reduced diagnostic specificity in clinically diagnosed atypical PSP cases-when applying the 2017 MDS criteria-compared to Richardson's syndrome cases. We independently replicated eight PSP risk variants in seven known loci (MAPT, MOBP, EIF2AK3, STX6, SLCO1A2, DUSP10 and APOE), and identified a novel locus in NFASC/CNTN2 (rs12744678 C: OR[95%CI] = 0.83[0.78-0.89]; p = 4.15<middle dot>10-08) after meta-analysis with a newly available Dutch cohort and publicly available summary statistics (3,099 PSP; 11,482 controls). Enrichment analysis and protein expression profiling highlighted oligodendrocyte function and myelination as likely contributors to PSP pathogenesis. Our findings broaden the genetic landscape of PSP and suggest potential therapeutic avenues focused on modulating neuron-oligodendrocyte interactions.