| Literature DB >> 30739198 |
Cyril Pottier1, Yingxue Ren2, Ralph B Perkerson1, Matt Baker1, Gregory D Jenkins3, Marka van Blitterswijk1, Mariely DeJesus-Hernandez1, Jeroen G J van Rooij4, Melissa E Murray1, Elizabeth Christopher1, Shannon K McDonnell3, Zachary Fogarty3, Anthony Batzler3, Shulan Tian3, Cristina T Vicente1, Billie Matchett1, Anna M Karydas5, Ging-Yuek Robin Hsiung6, Harro Seelaar4, Merel O Mol4, Elizabeth C Finger7, Caroline Graff8,9, Linn Öijerstedt8,9, Manuela Neumann10,11, Peter Heutink10,12, Matthis Synofzik10,12, Carlo Wilke10,12, Johannes Prudlo10,13, Patrizia Rizzu10, Javier Simon-Sanchez10,12, Dieter Edbauer14,15, Sigrun Roeber16, Janine Diehl-Schmid17, Bret M Evers18, Andrew King19,20, M Marsel Mesulam21, Sandra Weintraub21,22, Changiz Geula21, Kevin F Bieniek1,23, Leonard Petrucelli1, Geoffrey L Ahern24, Eric M Reiman25, Bryan K Woodruff26, Richard J Caselli26, Edward D Huey27, Martin R Farlow28, Jordan Grafman29, Simon Mead30, Lea T Grinberg5,31, Salvatore Spina5, Murray Grossman32, David J Irwin32, Edward B Lee33, EunRan Suh33, Julie Snowden34, David Mann35, Nilufer Ertekin-Taner1,36, Ryan J Uitti36, Zbigniew K Wszolek36, Keith A Josephs37, Joseph E Parisi37, David S Knopman37, Ronald C Petersen37, John R Hodges38, Olivier Piguet39, Ethan G Geier5, Jennifer S Yokoyama5, Robert A Rissman40,41, Ekaterina Rogaeva42, Julia Keith43,44, Lorne Zinman43, Maria Carmela Tartaglia42,45, Nigel J Cairns46, Carlos Cruchaga47, Bernardino Ghetti48, Julia Kofler49, Oscar L Lopez24,50, Thomas G Beach51, Thomas Arzberger14,16,52, Jochen Herms14,16, Lawrence S Honig53, Jean Paul Vonsattel54, Glenda M Halliday38,55, John B Kwok38,55, Charles L White18, Marla Gearing56, Jonathan Glass56, Sara Rollinson57, Stuart Pickering-Brown57, Jonathan D Rohrer58, John Q Trojanowski33, Vivianna Van Deerlin33, Eileen H Bigio21, Claire Troakes19, Safa Al-Sarraj19,20, Yan Asmann2, Bruce L Miller5, Neill R Graff-Radford36, Bradley F Boeve37, William W Seeley5,31, Ian R A Mackenzie59, John C van Swieten4, Dennis W Dickson1, Joanna M Biernacka3, Rosa Rademakers60.
Abstract
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.Entities:
Keywords: DPP6; HLA; Immunity; TBK1; UNC13A; Whole-genome sequencing FTLD-TDP
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Year: 2019 PMID： 30739198 PMCID： PMC6533145 DOI： 10.1007/s00401-019-01962-9
Source DB: PubMed Journal: Acta Neuropathol ISSN： 0001-6322 Impact factor: 17.088