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

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

doi:10.1038/s41431-025-01872-3

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

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

Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	960-965
Number of pages	6
Journal	European Journal of Human Genetics
Volume	33
Issue number	7
DOIs	https://doi.org/10.1038/s41431-025-01872-3
State	Published - Jul 2025

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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García-González, P., Rodrigo Lara, H., Compta, Y., Fernandez, M., van der Lee, S. J., de Rojas, I., Saiz, L., Painous, C., Camara, A., Muñoz, E., Marti, M. J., Valldeoriola, F., Puerta, R., Illán-Gala, I., Pagonabarraga, J., Dols-Icardo, O., Kulisevsky, J., Fortea, J., Lleó, A., ... Ruiz, A. (2025). A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC. European Journal of Human Genetics, 33(7), 960-965. https://doi.org/10.1038/s41431-025-01872-3

García-González, P, Rodrigo Lara, H, 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, Díaz Belloso, R, Muñoz-Delgado, L, Buiza Rueda, D, Gómez-Garre, P, Aldecoa, I, Aragonés, G, Hernandez Vara, J, Mendioroz, M, Pérez-Tur, J, Visser, PJ, den Braber, A, Papma, JM, Martín Montes, Á, 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, Á, Tàrraga, L, Real, LM, Royo, JL, Erro, ME, Guerrero, C, Corte Torres, D, Blázquez-Estrada, M, San Millán, B, Teijeira, S, Vilas Rolan, D, Hernández, I, Sánchez-Soblechero, A, de la Casa-Fages, B, Serrano López, S, Baviera-Muñoz, R, Lavín, A, Taipa, R, Amer, G, Martinez-Saez, E, Fernández-Matarrubia, M, Lage-Martínez, C, Álvarez, V, Molina-Porcel, L, Holstege, H, Mir, P, Belbin, O, Boada, M, Fernández, V, Bullido, MJ, Rábano, A, Sánchez-Juan, P & Ruiz, A 2025, 'A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC', European Journal of Human Genetics, vol. 33, no. 7, pp. 960-965. https://doi.org/10.1038/s41431-025-01872-3

@article{8bf597b2070d471bb755872c25fcf812,

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

abstract = "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{\textquoteright}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.",

author = "Pablo Garc{\'i}a-Gonz{\'a}lez and \{Rodrigo Lara\}, H{\'e}ctor and Yaroslau Compta and Manuel Fernandez and \{van der Lee\}, \{Sven J.\} and \{de Rojas\}, Itziar and Laura Saiz and Celia Painous and Ana Camara and Esteban Mu{\~n}oz and Marti, \{Maria J.\} and Francesc Valldeoriola and Raquel Puerta and Ignacio Ill{\'a}n-Gala and Javier Pagonabarraga and Oriol Dols-Icardo and Jaime Kulisevsky and Juan Fortea and Alberto Lle{\'o} and Claudia Oliv{\'e} and \{de Boer\}, \{Sterre C.M.\} and Marc Hulsman and Pijnenburg, \{Yolande A.L.\} and \{D{\'i}az Belloso\}, Rafael and Laura Mu{\~n}oz-Delgado and \{Buiza Rueda\}, Dolores and Pilar G{\'o}mez-Garre and Iban Aldecoa and Gemma Aragon{\'e}s and \{Hernandez Vara\}, Jorge and Maite Mendioroz and Jordi P{\'e}rez-Tur and Visser, \{Pieter Jelle\} and \{den Braber\}, Anouk and Papma, \{Janne M.\} and \{Mart{\'i}n Montes\}, {\'A}ngel and Eloy Rodriguez-Rodriguez and Josep Bl{\'a}zquez-Folch and Andrea Miguel and Fernando Garc{\'i}a-Guti{\'e}rrez and Amanda Cano and Sergi Valero and Marta Marqui{\'e} and Mar{\'i}a Capdevila-Bayo and Maitee Rosende-Roca and In{\'e}s Quintela and {\'A}ngel Carracedo and Llu{\'i}s T{\`a}rraga and Real, \{Luis M.\} and Royo, \{Jose Luis\} and Erro, \{Mar{\'i}a Elena\} and Carmen Guerrero and \{Corte Torres\}, Daniela and Marta Bl{\'a}zquez-Estrada and \{San Mill{\'a}n\}, Beatriz and Susana Teijeira and \{Vilas Rolan\}, Dolores and Isabel Hern{\'a}ndez and Antonio S{\'a}nchez-Soblechero and \{de la Casa-Fages\}, Beatriz and \{Serrano L{\'o}pez\}, Soledad and Raquel Baviera-Mu{\~n}oz and Amaya Lav{\'i}n and Ricardo Taipa and Guillermo Amer and Elena Martinez-Saez and Marta Fern{\'a}ndez-Matarrubia and Carmen Lage-Mart{\'i}nez and Victoria {\'A}lvarez and Laura Molina-Porcel and Henne Holstege and Pablo Mir and Olivia Belbin and Merc{\`e} Boada and Victoria Fern{\'a}ndez and Bullido, \{Mar{\'i}a J.\} and Alberto R{\'a}bano and Pascual S{\'a}nchez-Juan and Agust{\'i}n Ruiz",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to European Society of Human Genetics 2025.",

year = "2025",

month = jul,

doi = "10.1038/s41431-025-01872-3",

language = "English (US)",

volume = "33",

pages = "960--965",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "7",

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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

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.

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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 -

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

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