TY - JOUR
T1 - A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC
AU - Garcia-Gonzalez, Pablo
AU - Lara, Hector Rodrigo
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 - Munoz, Esteban
AU - Marti, Maria J.
AU - Valldeoriola, Francesc
AU - Puerta, Raquel
AU - Illan-Gala, Ignacio
AU - Pagonabarraga, Javier
AU - Dols-Icardo, Oriol
AU - Kulisevsky, Jaime
AU - Fortea, Juan
AU - Lleo, Alberto
AU - Olive, Claudia
AU - de Boer, Sterre C. M.
AU - Hulsman, Marc
AU - Pijnenburg, Yolande A. L.
AU - Belloso, Rafael Diaz
AU - Munoz-Delgado, Laura
AU - Rueda, Dolores Buiza
AU - Gomez-Garre, Pilar
AU - Aldecoa, Iban
AU - Aragones, Gemma
AU - Vara, Jorge Hernandez
AU - Mendioroz, Maite
AU - Perez-Tur, Jordi
AU - Visser, Pieter Jelle
AU - den Braber, Anouk
AU - Papma, Janne M.
AU - Montes, Angel Martin
AU - Rodriguez-Rodriguez, Eloy
AU - Blazquez-Folch, Josep
AU - Miguel, Andrea
AU - Garcia-Gutierrez, Fernando
AU - Cano, Amanda
AU - Valero, Sergi
AU - Marquie, Marta
AU - Capdevila-Bayo, Maria
AU - Rosende-Roca, Maitee
AU - Quintela, Ines
AU - Carracedo, Angel
AU - Tarraga, Lluis
AU - Real, Luis M.
AU - Royo, Jose Luis
AU - Et al.
AU - Ruiz, Agustín
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 = 4.1510-08) 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 = 4.1510-08) 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.
KW - TAU
KW - ALZHEIMERS
U2 - 10.1038/s41431-025-01872-3
DO - 10.1038/s41431-025-01872-3
M3 - Article
SN - 1018-4813
VL - 33
SP - 960
EP - 965
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -