一项关于进行性核上性麻痹的西班牙-葡萄牙全基因组关联研究揭示了神经束膜蛋白（NFASC）中的一个新风险位点。
A Spanish-Portuguese GWAS of progressive supranuclear palsy reveals a novel risk locus in NFASC.
作者信息
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
机构信息
Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain.
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
出版信息
Eur J Hum Genet. 2025 May 16. doi: 10.1038/s41431-025-01872-3.
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) 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.
进行性核上性麻痹（PSP）是一种罕见的4重复tau蛋白病，可导致行为、运动和认知异常。我们对西班牙和葡萄牙所有可用的临床和组织病理学PSP病例（N = 522）进行了基因分型，并开展了迄今为止伊比利亚人群最大规模的PSP全基因组关联研究（GWAS）。基因负担分析显示，与理查森综合征病例相比，在应用2017年MDS标准时，临床诊断的非典型PSP病例的诊断特异性降低。我们在七个已知基因座（MAPT、MOBP、EIF2AK3、STX6、SLCO1A2、DUSP10和APOE）中独立重复验证了八个PSP风险变异，并在与一个新获得的荷兰队列及公开可用的汇总统计数据（3099例PSP；11482例对照）进行荟萃分析后，在NFASC/CNTN2中鉴定出一个新基因座（rs12744678 C：优势比[95%置信区间]=0.83[0.78 - 0.89]；p = 4.15·10⁻¹⁰）。富集分析和蛋白质表达谱分析突出了少突胶质细胞功能和髓鞘形成可能是PSP发病机制的促成因素。我们的研究结果拓宽了PSP的遗传格局，并提出了以调节神经元 - 少突胶质细胞相互作用为重点的潜在治疗途径。
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