European journal of human genetics : EJHG · 2025

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

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García-González Pablo, Rodrigo Lara Héctor, Compta Yaroslau, Fernandez Manuel, van der Lee Sven J, de Rojas Itziar, Saiz Laura, Painous Celia, Camara Ana, Muñoz Esteban, Marti Maria J, Valldeoriola Francesc, Puerta Raquel, Illán-Gala Ignacio, Pagonabarraga Javier, Dols-Icardo Oriol, Kulisevsky Jaime, Fortea Juan, Lleó Alberto, Olivé Claudia, de Boer Sterre C M, Hulsman Marc, Pijnenburg Yolande A L, Díaz Belloso Rafael, Muñoz-Delgado Laura, Buiza Rueda Dolores, Gómez-Garre Pilar, Aldecoa Iban, Aragonés Gemma, Hernandez Vara Jorge, Mendioroz Maite, Pérez-Tur Jordi, Visser Pieter Jelle, den Braber Anouk, Papma Janne M, Martín Montes Ángel, Rodriguez-Rodriguez Eloy, Blázquez-Folch Josep, Miguel Andrea, García-Gutiérrez Fernando, Cano Amanda, Valero Sergi, Marquié Marta, Capdevila-Bayo María, Rosende-Roca Maitee, Quintela Inés, Carracedo Ángel, Tàrraga Lluís, Real Luis M, Royo Jose Luis, Erro María Elena, Guerrero Carmen, Corte Torres Daniela, Blázquez-Estrada Marta, San Millán Beatriz, Teijeira Susana, Vilas Rolan Dolores, Hernández Isabel, Sánchez-Soblechero Antonio, de la Casa-Fages Beatriz, Serrano López Soledad, Baviera-Muñoz Raquel, Lavín Amaya, Taipa Ricardo, Amer Guillermo, Martinez-Saez Elena, Fernández-Matarrubia Marta, Lage-Martínez Carmen, Álvarez Victoria, Molina-Porcel Laura, Holstege Henne, Mir Pablo, Belbin Olivia, Boada Mercè, Fernández Victoria, Bullido María J, Rábano Alberto, Sánchez-Juan Pascual, Ruiz Agustín

Аннотация

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.

Предметные рубрики MeSH

Humans Supranuclear Palsy, Progressive Spain Portugal Male Female Genome-Wide Association Study Aged Middle Aged Polymorphism, Single Nucleotide Genetic Predisposition to Disease

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

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Аннотация

Предметные рубрики MeSH