TY - JOUR
T1 - A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC
AU - García-González, Pablo
AU - Rodrigo Lara, Héctor
AU - Compta, Yaroslau
AU - Fernandez, Manuel
AU - van der Lee, Sven J.
AU - de Rojas, Itziar
AU - Saiz, Laura
AU - Painous, Celia
AU - Camara, Ana
AU - Muñoz, Esteban
AU - Marti, Maria J.
AU - Valldeoriola, Francesc
AU - Puerta, Raquel
AU - Illán-Gala, Ignacio
AU - Pagonabarraga, Javier
AU - Dols-Icardo, Oriol
AU - Kulisevsky, Jaime
AU - Fortea, Juan
AU - Lleó, Alberto
AU - Olivé, Claudia
AU - de Boer, Sterre C.M.
AU - Hulsman, Marc
AU - Pijnenburg, Yolande A.L.
AU - Díaz Belloso, Rafael
AU - Muñoz-Delgado, Laura
AU - Buiza Rueda, Dolores
AU - Gómez-Garre, Pilar
AU - Aldecoa, Iban
AU - Aragonés, Gemma
AU - Hernandez Vara, Jorge
AU - Mendioroz, Maite
AU - Pérez-Tur, Jordi
AU - Visser, Pieter Jelle
AU - den Braber, Anouk
AU - Papma, Janne M.
AU - Martín Montes, Ángel
AU - Rodriguez-Rodriguez, Eloy
AU - Blázquez-Folch, Josep
AU - Miguel, Andrea
AU - García-Gutiérrez, Fernando
AU - Cano, Amanda
AU - Valero, Sergi
AU - Marquié, Marta
AU - Capdevila-Bayo, María
AU - Rosende-Roca, Maitee
AU - Quintela, Inés
AU - Carracedo, Ángel
AU - Tàrraga, Lluís
AU - Real, Luis M.
AU - Royo, Jose Luis
AU - Erro, María Elena
AU - Guerrero, Carmen
AU - Corte Torres, Daniela
AU - Blázquez-Estrada, Marta
AU - San Millán, Beatriz
AU - Teijeira, Susana
AU - Vilas Rolan, Dolores
AU - Hernández, Isabel
AU - Sánchez-Soblechero, Antonio
AU - de la Casa-Fages, Beatriz
AU - Serrano López, Soledad
AU - Baviera-Muñoz, Raquel
AU - Lavín, Amaya
AU - Taipa, Ricardo
AU - Amer, Guillermo
AU - Martinez-Saez, Elena
AU - Fernández-Matarrubia, Marta
AU - Lage-Martínez, Carmen
AU - Álvarez, Victoria
AU - Molina-Porcel, Laura
AU - Holstege, Henne
AU - Mir, Pablo
AU - Belbin, Olivia
AU - Boada, Mercè
AU - Fernández, Victoria
AU - Bullido, María J.
AU - Rábano, Alberto
AU - Sánchez-Juan, Pascual
AU - Ruiz, Agustín
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to European Society of Human Genetics 2025.
PY - 2025/7
Y1 - 2025/7
N2 - 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 = 4.15·10−08) 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.
AB - 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 = 4.15·10−08) 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.
UR - https://www.scopus.com/pages/publications/105005103705
UR - https://www.scopus.com/pages/publications/105005103705#tab=citedBy
U2 - 10.1038/s41431-025-01872-3
DO - 10.1038/s41431-025-01872-3
M3 - Article
C2 - 40379966
AN - SCOPUS:105005103705
SN - 1018-4813
VL - 33
SP - 960
EP - 965
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -