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The present work has been performed as part of the Doctoral thesis of Pablo Garcia-Gonzalez at the University of Barcelona (Barcelona, Spain). We would like to thank patients and controls who participated in this project. Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. We are grateful to the Biomedic Diagnostic Center (CBD) of the Hospital Clinic de Barcelona for access to, and assistance with, FLUOSTAR Omega equipment and RT-QuIC experiments (Drs. Raquel Ruiz and Laura Naranco). Hospital Clinic de Barcelona receives support from the CERCA programme from Generalitat de Catalunya (Catalan government). Several authors of this manuscript are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510, as well as CIBERNED (CB06/05/0018-ISCIII). We acknowledge the Biobank of the University of Navarra for its collaboration. We thank all study participants and all personnel involved in data collection for the contributing studies. Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The chair of Wiesje van der Flier is supported by the Pasman stichting. The clinical database structure was developed with funding from Stichting Dioraphte. The work in this manuscript was carried out on the Snellius supercomputer, which is embedded in the Dutch national e-infrastructure with the support of SURF Cooperative. Computing hours were granted in 2016, 2017, 2018 and 2019 to H. Holstege by the Dutch Research Council (project name: '100plus'; project numbers 15318 and 17232). Samples and data from patients included in this study were provided by the Vall d'Hebron University Hospital Biobank (PT20/00107), integrated in the Spanish National Biobanks Network, and they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committees. We are indebted to the Biobank-Hospital Clinic-FRCB-IDIBAPS for samples and data procurement.

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

Publicated to:EUROPEAN JOURNAL OF HUMAN GENETICS (): - - 2025-05-16 (), DOI: 10.1038/s41431-025-01872-3

Authors: 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

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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 = 4.1510-08) 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.

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