TY - JOUR
T1 - 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
AU - Pottier, Cyril
AU - Ren, Yingxue
AU - Perkerson, Ralph B.
AU - Baker, Matt
AU - Jenkins, Gregory D.
AU - van Blitterswijk, Marka
AU - DeJesus-Hernandez, Mariely
AU - van Rooij, Jeroen G.J.
AU - Murray, Melissa E.
AU - Christopher, Elizabeth
AU - McDonnell, Shannon K.
AU - Fogarty, Zachary
AU - Batzler, Anthony
AU - Tian, Shulan
AU - Vicente, Cristina T.
AU - Matchett, Billie
AU - Karydas, Anna M.
AU - Hsiung, Ging Yuek Robin
AU - Seelaar, Harro
AU - Mol, Merel O.
AU - Finger, Elizabeth C.
AU - Graff, Caroline
AU - Öijerstedt, Linn
AU - Neumann, Manuela
AU - Heutink, Peter
AU - Synofzik, Matthis
AU - Wilke, Carlo
AU - Prudlo, Johannes
AU - Rizzu, Patrizia
AU - Simon-Sanchez, Javier
AU - Edbauer, Dieter
AU - Roeber, Sigrun
AU - Diehl-Schmid, Janine
AU - Evers, Bret M.
AU - King, Andrew
AU - Mesulam, M. Marsel
AU - Weintraub, Sandra
AU - Geula, Changiz
AU - Bieniek, Kevin F.
AU - Petrucelli, Leonard
AU - Ahern, Geoffrey L.
AU - Reiman, Eric M.
AU - Woodruff, Bryan K.
AU - Caselli, Richard J.
AU - Huey, Edward D.
AU - Farlow, Martin R.
AU - Grafman, Jordan
AU - Mead, Simon
AU - Grinberg, Lea T.
AU - Spina, Salvatore
AU - Grossman, Murray
AU - Irwin, David J.
AU - Lee, Edward B.
AU - Suh, Eun Ran
AU - Snowden, Julie
AU - Mann, David
AU - Ertekin-Taner, Nilufer
AU - Uitti, Ryan J.
AU - Wszolek, Zbigniew K.
AU - Josephs, Keith A.
AU - Parisi, Joseph E.
AU - Knopman, David S.
AU - Petersen, Ronald C.
AU - Hodges, John R.
AU - Piguet, Olivier
AU - Geier, Ethan G.
AU - Yokoyama, Jennifer S.
AU - Rissman, Robert A.
AU - Rogaeva, Ekaterina
AU - Keith, Julia
AU - Zinman, Lorne
AU - Tartaglia, Maria Carmela
AU - Cairns, Nigel J.
AU - Cruchaga, Carlos
AU - Ghetti, Bernardino
AU - Kofler, Julia
AU - Lopez, Oscar L.
AU - Beach, Thomas G.
AU - Arzberger, Thomas
AU - Herms, Jochen
AU - Honig, Lawrence S.
AU - Vonsattel, Jean Paul
AU - Halliday, Glenda M.
AU - Kwok, John B.
AU - White, Charles L.
AU - Gearing, Marla
AU - Glass, Jonathan
AU - Rollinson, Sara
AU - Pickering-Brown, Stuart
AU - Rohrer, Jonathan D.
AU - Trojanowski, John Q.
AU - Van Deerlin, Vivianna
AU - Bigio, Eileen H.
AU - Troakes, Claire
AU - Al-Sarraj, Safa
AU - Asmann, Yan
AU - Miller, Bruce L.
AU - Graff-Radford, Neill R.
AU - Boeve, Bradley F.
AU - Seeley, William W.
AU - Mackenzie, Ian R.A.
AU - van Swieten, John C.
AU - Dickson, Dennis W.
AU - Biernacka, Joanna M.
AU - Rademakers, Rosa
N1 - Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - DPP6
KW - HLA
KW - Immunity
KW - TBK1
KW - UNC13A
KW - Whole-genome sequencing FTLD-TDP
UR - http://www.scopus.com/inward/record.url?scp=85061326203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061326203&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-01962-9
DO - 10.1007/s00401-019-01962-9
M3 - Article
C2 - 30739198
AN - SCOPUS:85061326203
SN - 0001-6322
VL - 137
SP - 879
EP - 899
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 6
ER -