학술논문
Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
Document Type
article
Author
Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B; Baker, Matt; Jenkins, Gregory D; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen GJ; Murray, Melissa E; Christopher, Elizabeth; McDonnell, Shannon K; Fogarty, Zachary; Batzler, Anthony; Tian, Shulan; Vicente, Cristina T; Matchett, Billie; Karydas, Anna M; Hsiung, Ging-Yuek Robin; Seelaar, Harro; Mol, Merel O; Finger, Elizabeth C; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Wilke, Carlo; Prudlo, Johannes; Rizzu, Patrizia; Simon-Sanchez, Javier; Edbauer, Dieter; Roeber, Sigrun; Diehl-Schmid, Janine; Evers, Bret M; King, Andrew; Mesulam, M Marsel; Weintraub, Sandra; Geula, Changiz; Bieniek, Kevin F; Petrucelli, Leonard; Ahern, Geoffrey L; Reiman, Eric M; Woodruff, Bryan K; Caselli, Richard J; Huey, Edward D; Farlow, Martin R; Grafman, Jordan; Mead, Simon; Grinberg, Lea T; Spina, Salvatore; Grossman, Murray; Irwin, David J; Lee, Edward B; Suh, EunRan; Snowden, Julie; Mann, David; Ertekin-Taner, Nilufer; Uitti, Ryan J; Wszolek, Zbigniew K; Josephs, Keith A; Parisi, Joseph E; Knopman, David S; Petersen, Ronald C; Hodges, John R; Piguet, Olivier; Geier, Ethan G; Yokoyama, Jennifer S; Rissman, Robert A; Rogaeva, Ekaterina; Keith, Julia; Zinman, Lorne; Tartaglia, Maria Carmela; Cairns, Nigel J; Cruchaga, Carlos; Ghetti, Bernardino; Kofler, Julia; Lopez, Oscar L; Beach, Thomas G; Arzberger, Thomas; Herms, Jochen; Honig, Lawrence S; Vonsattel, Jean Paul; Halliday, Glenda M; Kwok, John B; White, Charles L; Gearing, Marla; Glass, Jonathan; Rollinson, Sara; Pickering-Brown, Stuart; Rohrer, Jonathan D; Trojanowski, John Q; Van Deerlin, Vivianna; Bigio, Eileen H; Troakes, Claire; Al-Sarraj, Safa; Asmann, Yan; Miller, Bruce L; Graff-Radford, Neill R; Boeve, Bradley F; Seeley, William W
Source
Acta Neuropathologica. 137(6)
Subject
Language
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.