Pottier Cyril, Küçükali Fahri, Baker Matt, Batzler Anthony, Jenkins Gregory D, van Blitterswijk Marka, Vicente Cristina T, De Coster Wouter, Wynants Sarah, Van de Walle Pieter, Ross Owen A, Murray Melissa E, Faura Júlia, Haggarty Stephen J, van Rooij Jeroen Gj, Mol Merel O, Hsiung Ging-Yuek R, Graff Caroline, Öijerstedt Linn, Neumann Manuela, Asmann Yan, McDonnell Shannon K, Baheti Saurabh, Josephs Keith A, Whitwell Jennifer L, Bieniek Kevin F, Forsberg Leah, Heuer Hilary, Lago Argentina Lario, Geier Ethan G, Yokoyama Jennifer S, Oddi Alexis P, Flanagan Margaret, Mao Qinwen, Hodges John R, Kwok John B, Domoto-Reilly Kimiko, Synofzik Matthis, Wilke Carlo, Onyike Chiadi, Dickerson Bradford C, Evers Bret M, Dugger Brittany N, Munoz David G, Keith Julia, Zinman Lorne, Rogaeva Ekaterina, Suh EunRan, Gefen Tamar, Geula Changiz, Weintraub Sandra, Diehl-Schmid Janine, Farlow Martin R, Edbauer Dieter, Woodruff Bryan K, Caselli Richard J, Donker Kaat Laura L, Huey Edward D, Reiman Eric M, Mead Simon, King Andrew, Roeber Sigrun, Nana Alissa L, Ertekin-Taner Nilufer, Knopman David S, Petersen Ronald C, Petrucelli Leonard, Uitti Ryan J, Wszolek Zbigniew K, Ramos Eliana Marisa, Grinberg Lea T, Gorno Tempini Maria Luisa, Rosen Howard J, Spina Salvatore, Piguet Olivier, Grossman Murray, Trojanowski John Q, Keene Dirk C, Lee-Way Jin, Prudlo Johannes, Geschwind Daniel H, Rissman Robert A, Cruchaga Carlos, Ghetti Bernardino, Halliday Glenda M, Beach Thomas G, Serrano Geidy E, Arzberger Thomas, Herms Jochen, Boxer Adam L, Honig Lawrence S, Vonsattel Jean P, Lopez Oscar L, Kofler Julia, White Charles L, Gearing Marla, Glass Jonathan, Rohrer Jonathan D, Irwin David J, Lee Edward B, Van Deerlin Vivianna, Castellani Rudolph, Mesulam Marsel M, Tartaglia Maria C, Finger Elizabeth C, Troakes Claire, Al-Sarraj Safa, Miller Bruce L, Seelaar Harro, Graff-Radford Neill R, Boeve Bradley F, Mackenzie Ian Ra, van Swieten John C, Seeley William W, Sleegers Kristel, Dickson Dennis W, Biernacka Joanna M, Rademakers Rosa
medRxiv. 2024 Jun 25:2024.06.24.24309088. doi: 10.1101/2024.06.24.24309088.
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm as the strongest overall FTLD-TDP risk factor and identify as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed and identified , , and as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
伴有TAR DNA结合蛋白43神经元内含物的额颞叶变性（FTLD-TDP）是一种致命的神经退行性疾病，目前仅确定了有限数量的风险基因座。作为国际FTLD-TDP全基因组测序联盟的一部分，我们报告了我们全面的全基因组关联研究，包括985例病例和3153例对照，并与来自美国、欧洲和澳大利亚26个机构/脑库的痴呆症测序队列进行了荟萃分析。我们确认了作为FTLD-TDP最强的总体风险因素，并确定了作为一种新的FTLD-TDP风险因素。在亚组分析中，我们首次进一步确定了三种主要FTLD-TDP病理亚型（A、B和C）各自特有的全基因组显著基因座，以及不同组织、脑区和神经元亚型中风险基因座的富集，表明每种亚型都有不同的疾病病因。罕见变异分析确认了并确定了 、 、 和 作为新的亚型特异性FTLD-TDP风险基因，进一步突出了先天和适应性免疫以及Notch信号通路在FTLD-TDP中的作用，具有潜在的诊断和新的治疗意义。
