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

Cyril Pottier, Yingxue Ren, Ralph B. Perkerson, Matt Baker, Gregory D. Jenkins, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Jeroen G.J. van Rooij, Melissa E. Murray, Elizabeth Christopher, Shannon K. McDonnell, Zachary Fogarty, Anthony Batzler, Shulan Tian, Cristina T. Vicente, Billie Matchett, Anna M. Karydas, Ging Yuek Robin Hsiung, Harro Seelaar, Merel O. Mol & 85 others Elizabeth C. Finger, Caroline Graff, Linn Öijerstedt, Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Johannes Prudlo, Patrizia Rizzu, Javier Simon-Sanchez, Dieter Edbauer, Sigrun Roeber, Janine Diehl-Schmid, Bret M. Evers, Andrew King, Marek-Marsel Mesulam, Sandra Weintraub, Changiz Geula, Kevin F. Bieniek, Leonard Petrucelli, Geoffrey L. Ahern, Eric M. Reiman, Bryan K. Woodruff, Richard J. Caselli, Edward D. Huey, Martin R. Farlow, Jordan Henry Grafman, Simon Mead, Lea T. Grinberg, Salvatore Spina, Murray Grossman, David J. Irwin, Edward B. Lee, Eun Ran Suh, Julie Snowden, David Mann, Nilufer Ertekin-Taner, Ryan J. Uitti, Zbigniew K. Wszolek, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, John R. Hodges, Olivier Piguet, Ethan G. Geier, Jennifer S. Yokoyama, Robert A. Rissman, Ekaterina Rogaeva, Julia Keith, Lorne Zinman, Maria Carmela Tartaglia, Nigel J. Cairns, Carlos Cruchaga, Bernardino Ghetti, Julia Kofler, Oscar L. Lopez, Thomas G. Beach, Thomas Arzberger, Jochen Herms, Lawrence S. Honig, Jean Paul Vonsattel, Glenda M. Halliday, John B. Kwok, Charles L. White, Marla Gearing, Jonathan Glass, Sara Rollinson, Stuart Pickering-Brown, Jonathan D. Rohrer, John Q. Trojanowski, Vivianna Van Deerlin, Eileen H Bigio, Claire Troakes, Safa Al-Sarraj, Yan Asmann, Bruce L. Miller, Neill R. Graff-Radford, Bradley F. Boeve, William W. Seeley, Ian R.A. Mackenzie, John C. van Swieten, Dennis W. Dickson, Joanna M. Biernacka, Rosa Rademakers*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)879-899
Number of pages21
JournalActa Neuropathologica
Volume137
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Frontotemporal Lobar Degeneration
Frontotemporal Dementia
Genome
Genes
Mutation
DNA-Binding Proteins

Keywords

  • DPP6
  • HLA
  • Immunity
  • TBK1
  • UNC13A
  • Whole-genome sequencing FTLD-TDP

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Pottier, Cyril ; Ren, Yingxue ; Perkerson, Ralph B. ; Baker, Matt ; Jenkins, Gregory D. ; van Blitterswijk, Marka ; DeJesus-Hernandez, Mariely ; van Rooij, Jeroen G.J. ; 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, Marek-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 Henry ; Mead, Simon ; Grinberg, Lea T. ; Spina, Salvatore ; Grossman, Murray ; Irwin, David J. ; Lee, Edward B. ; Suh, Eun Ran ; 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. ; Mackenzie, Ian R.A. ; van Swieten, John C. ; Dickson, Dennis W. ; Biernacka, Joanna M. ; Rademakers, Rosa. / 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. In: Acta Neuropathologica. 2019 ; Vol. 137, No. 6. pp. 879-899.
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title = "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",
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.",
keywords = "DPP6, HLA, Immunity, TBK1, UNC13A, Whole-genome sequencing FTLD-TDP",
author = "Cyril Pottier and Yingxue Ren and Perkerson, {Ralph B.} and Matt Baker and Jenkins, {Gregory D.} and {van Blitterswijk}, Marka and Mariely DeJesus-Hernandez and {van Rooij}, {Jeroen G.J.} and Murray, {Melissa E.} and Elizabeth Christopher and McDonnell, {Shannon K.} and Zachary Fogarty and Anthony Batzler and Shulan Tian and Vicente, {Cristina T.} and Billie Matchett and Karydas, {Anna M.} and Hsiung, {Ging Yuek Robin} and Harro Seelaar and Mol, {Merel O.} and Finger, {Elizabeth C.} and Caroline Graff and Linn {\"O}ijerstedt and Manuela Neumann and Peter Heutink and Matthis Synofzik and Carlo Wilke and Johannes Prudlo and Patrizia Rizzu and Javier Simon-Sanchez and Dieter Edbauer and Sigrun Roeber and Janine Diehl-Schmid and Evers, {Bret M.} and Andrew King and Marek-Marsel Mesulam and Sandra Weintraub and Changiz Geula and Bieniek, {Kevin F.} and Leonard Petrucelli and Ahern, {Geoffrey L.} and Reiman, {Eric M.} and Woodruff, {Bryan K.} and Caselli, {Richard J.} and Huey, {Edward D.} and Farlow, {Martin R.} and Grafman, {Jordan Henry} and Simon Mead and Grinberg, {Lea T.} and Salvatore Spina and Murray Grossman and Irwin, {David J.} and Lee, {Edward B.} and Suh, {Eun Ran} and Julie Snowden and David Mann and Nilufer Ertekin-Taner and Uitti, {Ryan J.} and Wszolek, {Zbigniew K.} and Josephs, {Keith A.} and Parisi, {Joseph E.} and Knopman, {David S.} and Petersen, {Ronald C.} and Hodges, {John R.} and Olivier Piguet and Geier, {Ethan G.} and Yokoyama, {Jennifer S.} and Rissman, {Robert A.} and Ekaterina Rogaeva and Julia Keith and Lorne Zinman and Tartaglia, {Maria Carmela} and Cairns, {Nigel J.} and Carlos Cruchaga and Bernardino Ghetti and Julia Kofler and Lopez, {Oscar L.} and Beach, {Thomas G.} and Thomas Arzberger and Jochen Herms and Honig, {Lawrence S.} and Vonsattel, {Jean Paul} and Halliday, {Glenda M.} and Kwok, {John B.} and White, {Charles L.} and Marla Gearing and Jonathan Glass and Sara Rollinson and Stuart Pickering-Brown and Rohrer, {Jonathan D.} and Trojanowski, {John Q.} and {Van Deerlin}, Vivianna and Bigio, {Eileen H} and Claire Troakes and Safa Al-Sarraj and Yan Asmann and Miller, {Bruce L.} and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Seeley, {William W.} and Mackenzie, {Ian R.A.} and {van Swieten}, {John C.} and Dickson, {Dennis W.} and Biernacka, {Joanna M.} and Rosa Rademakers",
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language = "English (US)",
volume = "137",
pages = "879--899",
journal = "Acta Neuropathologica",
issn = "0001-6322",
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Pottier, C, Ren, Y, Perkerson, RB, Baker, M, Jenkins, GD, van Blitterswijk, M, DeJesus-Hernandez, M, van Rooij, JGJ, Murray, ME, Christopher, E, McDonnell, SK, Fogarty, Z, Batzler, A, Tian, S, Vicente, CT, Matchett, B, Karydas, AM, Hsiung, GYR, Seelaar, H, Mol, MO, Finger, EC, Graff, C, Öijerstedt, L, Neumann, M, Heutink, P, Synofzik, M, Wilke, C, Prudlo, J, Rizzu, P, Simon-Sanchez, J, Edbauer, D, Roeber, S, Diehl-Schmid, J, Evers, BM, King, A, Mesulam, M-M, Weintraub, S, Geula, C, Bieniek, KF, Petrucelli, L, Ahern, GL, Reiman, EM, Woodruff, BK, Caselli, RJ, Huey, ED, Farlow, MR, Grafman, JH, Mead, S, Grinberg, LT, Spina, S, Grossman, M, Irwin, DJ, Lee, EB, Suh, ER, Snowden, J, Mann, D, Ertekin-Taner, N, Uitti, RJ, Wszolek, ZK, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC, Hodges, JR, Piguet, O, Geier, EG, Yokoyama, JS, Rissman, RA, Rogaeva, E, Keith, J, Zinman, L, Tartaglia, MC, Cairns, NJ, Cruchaga, C, Ghetti, B, Kofler, J, Lopez, OL, Beach, TG, Arzberger, T, Herms, J, Honig, LS, Vonsattel, JP, Halliday, GM, Kwok, JB, White, CL, Gearing, M, Glass, J, Rollinson, S, Pickering-Brown, S, Rohrer, JD, Trojanowski, JQ, Van Deerlin, V, Bigio, EH, Troakes, C, Al-Sarraj, S, Asmann, Y, Miller, BL, Graff-Radford, NR, Boeve, BF, Seeley, WW, Mackenzie, IRA, van Swieten, JC, Dickson, DW, Biernacka, JM & Rademakers, R 2019, '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', Acta Neuropathologica, vol. 137, no. 6, pp. 879-899. https://doi.org/10.1007/s00401-019-01962-9

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. / Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen G.J.; 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, Marek-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 Henry; Mead, Simon; Grinberg, Lea T.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, Eun Ran; 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.; Mackenzie, Ian R.A.; van Swieten, John C.; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa.

In: Acta Neuropathologica, Vol. 137, No. 6, 01.06.2019, p. 879-899.

Research output: Contribution to journalArticle

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, Marek-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 Henry

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

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

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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

VL - 137

SP - 879

EP - 899

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -