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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. PerkersonIII
  • 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
  • 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
  • M. 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 Grafman
  • Simon Mead
  • Lea T. Grinberg
  • Salvatore Spina
  • Murray Grossman
  • David J. Irwin
  • Edward B. Lee
  • EunRan 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. WhiteIII
  • 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 RademakersEmail author
Original Paper

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

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

Notes

Acknowledgements

We thank all colleagues and staff at the participating centres for their help with recruitment of patients. Specifically, we thank Drs. Etty P. Cortes, Allan Levey, James Lah, Chad Hales, William Hu, Inger Nennesmo, Håkan Thonberg, Huei-Hsin Chiang, Ivy and Jeffrey Metcalf, David Lacomis, Nick Fox, Martin Rossor, Jason Warren, Michael DeTure. We also thank Virginia Phillips, Linda Rousseau, Monica Casey-Castanedes, Pheth Sengdy, Alice Fok, Charlotte Forsell, Anna-Karin Lindström, Veronika Kaltenbrunn, Brigitte Kraft, Vanessa Boll, Chan Foong. This work was supported by the NIH from NIA: P50 AG008702 (LSH, J-PV, EPC); P50 AG025688 (MG and JDG); P30 AG010133 (BG, MF, JG, EDH); P30 AG013854 (EB, MM, SW,CG); R01 AG051848 and P50 AG005131 (RAR); P01 AG017586, P30 AG01024, U01 AG052943 (VVD, MG, DJI, EBL, JQT, ES); P50 AG005133 (JK, OLL), P30 AG012300 (CLWIII, BME); P50 AG005681, P01 AG003991 and U01 AG058922 (NJC, CC); P30 AG019610 (EMR); UO1 AG006786 and RO1 AG041797 (BFB); R01 AG037491 (KAJ); P50 AG016574 (RCP, BFB, RR, DWD, DSK, NRG-R); U01 AG046139 (NE-T); the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects U01 AG 045390 (BFB); K01 AG049152 (JSY). In addition part of the project was supported by the NIH from NIDCD: R01 DC008552 (RAR); and by the VA: I01 BX003040 (RAR). This research was supported by the University of Pittsburgh Brain Institute (JK, OLL); Carl B. and Florence E. King Foundation, McCune Foundation, Winspear Family Center for Research on the Neuropathology of Alzheimer Disease (CLWIII, BME); Arizona Department of Health Services contract #211002, Arizona Biomedical Research Commission contracts #4001, #0011, #05-901, #1001, the Michael J. Fox Foundation for Parkinson’s Research, Mayo Clinic Foundation and Sun Health Foundation (TGB). This work was supported by the NIH from NINDS: R35 NS097261 (RR); UH3/UG3 NS103870 (RR); U54 NS092089 (BFB, ALB); P01 NS084974 (DWD); R01 NS080820 (N.E-T); P50 NS072187 (ZKW); R01 NS076837 (EDH), P30 NS055077 (MG), U24 NS072026 (TGB); R01 NS085770 (CG). We thank the Mayo Clinic Center of Individualized Medicine for collection and sequencing of the Mayo Clinic Biobank samples. This work was further supported by grants from the Consortium for Frontotemporal dementia (RR), the Bluefield Project to Cure FTD (RR), the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program and the Little Family Foundation (BFB). Whole-genome sequencing was in part funded through the Rainwater Charitable Foundation (JSY). The Columbia University Brain Bank is supported by NIH Grant NIH/NIA P50 AG008702 (ADRC). The brain samples from the Netherlands were obtained from the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All material has been collected from donors for or for whom a written informed consent for a brain autopsy and the use of the material and clinical information for research purposes had been obtained by the NBB. Whole-genome sequencing of Dutch samples was supported by the “Gieskes-Strijbis foundation” as project “Semantic dementia unraveled” and through the “2bike4alzheimer” initiative by the “Alzheimer Netherlands foundation” as project “WE.09-2017-05” (JCvS, HS, JGJvR, MOM). Tissue samples were supplied by the London Neurodegenerative Diseases Brain bank, which receives funding from the Medical Research Council UK and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society (CT, SA-S, AK). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1), an NIHR Rare Disease Translational Research Collaboration fellowship (BRC149/NS/MH), the Bluefield Project, the MRC UK GENFI Grant (MR/M023664/1), the NIHR UCL/H Biomedical Research Centre, Alzheimer’s Research UK and the Alzheimer’s Society. SM is an NIHR senior investigator and is funded by the UK Medical Research Council and the NIHR UCL/H Biomedical Research Centre. SP-B was supported by the MRC Grant G0701441. The study was in also supported in part by institutional grants from the DZNE for “DZNE Brain Bank” and “Frontotemporal lobar degeneration: From basic mechanisms and target identification to translational and clinical approaches/Clinical Project” (MNPH, PR, JS-S, MS, JP). The work was also supported by the Hans und Ilse Breuer Foundation, Munich Cluster of Systems Neurology (SyNergy), European Community’s Health Seventh Framework Programme under Grant agreement 617198 [DPR-MODELS] (TA, DE, JH, SR). CW was supported by the fortüne program of the University of Tübingen (#2488-0-0). Research was supported by Grants provided by the Swedish research Council (Dnr 521-2010-3134, 529-2014-7504, 2015-02926), Alzheimer Foundation Sweden, Brain Foundation Sweden, Swedish FTD Initiative- Schörling foundation, Swedish Brain Power, Karolinska Institutet doctoral founding, Galma Tjänarinnor, Stohnes Foundation, Dementia Foundation Sweden and the Stockholm County Council (ALF-project). The brain pathology was provided through the Brain Bank at Karolinska Institutet which was financially supported by Karolinska Institutet StratNeuro, Swedish Brain Power, Stockholm County Council core facility funding (CG, LO). This work was also funded through the Canadian Consortium on Neurodegeneration in Aging (ER); in particular from CCNA #137794 (RG-Y, IRM); CIHR Operating Grant #327387 (ECF); #179009 (RG-Y, IRM). GMH, JBK, JRH, OP—The Sydney Brain Bank is funded by Neuroscience Research Australia and the University of New South Wales. The ForeFront Brain and Mind project team a large collaborative research group dedicated to the study of neurodegenerative diseases and funded by the National Health and Medical Research Council of Australia Program Grant (#1132524), Dementia Research Team Grant (#1095127), NeuroSleep Centre of Research Excellence (#1060992), and the ARC Centre of Excellence in Cognition and its Disorders Memory Program (CE10001021). OP is supported by a NHMRC Senior Research Fellowship (#1103258). GMH is supported by a NHMRC Senior Principal Research Fellowship (#1079679).

Compliance with ethical standards

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Cyril Pottier
    • 1
  • Yingxue Ren
    • 2
  • Ralph B. PerkersonIII
    • 1
  • Matt Baker
    • 1
  • Gregory D. Jenkins
    • 3
  • Marka van Blitterswijk
    • 1
  • Mariely DeJesus-Hernandez
    • 1
  • Jeroen G. J. van Rooij
    • 4
  • Melissa E. Murray
    • 1
  • Elizabeth Christopher
    • 1
  • Shannon K. McDonnell
    • 3
  • Zachary Fogarty
    • 3
  • Anthony Batzler
    • 3
  • Shulan Tian
    • 3
  • Cristina T. Vicente
    • 1
  • Billie Matchett
    • 1
  • Anna M. Karydas
    • 5
  • Ging-Yuek Robin Hsiung
    • 6
  • Harro Seelaar
    • 4
  • Merel O. Mol
    • 4
  • Elizabeth C. Finger
    • 7
  • Caroline Graff
    • 8
    • 9
  • Linn Öijerstedt
    • 8
    • 9
  • Manuela Neumann
    • 10
    • 11
  • Peter Heutink
    • 10
    • 12
  • Matthis Synofzik
    • 10
    • 12
  • Carlo Wilke
    • 10
    • 12
  • Johannes Prudlo
    • 10
    • 13
  • Patrizia Rizzu
    • 10
  • Javier Simon-Sanchez
    • 10
    • 12
  • Dieter Edbauer
    • 14
    • 15
  • Sigrun Roeber
    • 16
  • Janine Diehl-Schmid
    • 17
  • Bret M. Evers
    • 18
  • Andrew King
    • 19
    • 20
  • M. Marsel Mesulam
    • 21
  • Sandra Weintraub
    • 21
    • 22
  • Changiz Geula
    • 21
  • Kevin F. Bieniek
    • 1
    • 23
  • Leonard Petrucelli
    • 1
  • Geoffrey L. Ahern
    • 24
  • Eric M. Reiman
    • 25
  • Bryan K. Woodruff
    • 26
  • Richard J. Caselli
    • 26
  • Edward D. Huey
    • 27
  • Martin R. Farlow
    • 28
  • Jordan Grafman
    • 29
  • Simon Mead
    • 30
  • Lea T. Grinberg
    • 5
    • 31
  • Salvatore Spina
    • 5
  • Murray Grossman
    • 32
  • David J. Irwin
    • 32
  • Edward B. Lee
    • 33
  • EunRan Suh
    • 33
  • Julie Snowden
    • 34
  • David Mann
    • 35
  • Nilufer Ertekin-Taner
    • 1
    • 36
  • Ryan J. Uitti
    • 36
  • Zbigniew K. Wszolek
    • 36
  • Keith A. Josephs
    • 37
  • Joseph E. Parisi
    • 37
  • David S. Knopman
    • 37
  • Ronald C. Petersen
    • 37
  • John R. Hodges
    • 38
  • Olivier Piguet
    • 39
  • Ethan G. Geier
    • 5
  • Jennifer S. Yokoyama
    • 5
  • Robert A. Rissman
    • 40
    • 41
  • Ekaterina Rogaeva
    • 42
  • Julia Keith
    • 43
    • 44
  • Lorne Zinman
    • 43
  • Maria Carmela Tartaglia
    • 42
    • 45
  • Nigel J. Cairns
    • 46
  • Carlos Cruchaga
    • 47
  • Bernardino Ghetti
    • 48
  • Julia Kofler
    • 49
  • Oscar L. Lopez
    • 50
    • 24
  • Thomas G. Beach
    • 51
  • Thomas Arzberger
    • 52
    • 14
    • 16
  • Jochen Herms
    • 14
    • 16
  • Lawrence S. Honig
    • 53
  • Jean Paul Vonsattel
    • 54
  • Glenda M. Halliday
    • 38
    • 55
  • John B. Kwok
    • 38
    • 55
  • Charles L. WhiteIII
    • 18
  • Marla Gearing
    • 56
  • Jonathan Glass
    • 56
  • Sara Rollinson
    • 57
  • Stuart Pickering-Brown
    • 57
  • Jonathan D. Rohrer
    • 58
  • John Q. Trojanowski
    • 33
  • Vivianna Van Deerlin
    • 33
  • Eileen H. Bigio
    • 21
  • Claire Troakes
    • 19
  • Safa Al-Sarraj
    • 19
    • 20
  • Yan Asmann
    • 2
  • Bruce L. Miller
    • 5
  • Neill R. Graff-Radford
    • 36
  • Bradley F. Boeve
    • 37
  • William W. Seeley
    • 5
    • 31
  • Ian R. A. Mackenzie
    • 59
  • John C. van Swieten
    • 4
  • Dennis W. Dickson
    • 1
  • Joanna M. Biernacka
    • 3
  • Rosa Rademakers
    • 1
    Email author
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Department of Health Sciences ResearchMayo ClinicJacksonvilleUSA
  3. 3.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  4. 4.Department of NeurologyErasmus Medical CenterRotterdamThe Netherlands
  5. 5.Department of Neurology, Memory and Aging CenterUniversity of CaliforniaSan FranciscoUSA
  6. 6.Division of Neurology, Department of MedicineUniversity of British ColumbiaVancouverCanada
  7. 7.Department of Clinical Neurological Sciences, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada
  8. 8.Division of Neurogeriatrics, Department NVSKarolinska InstitutetSolnaSweden
  9. 9.Theme Aging, Unit for Hereditary DementiasKarolinska University HospitalSolnaSweden
  10. 10.German Center for Neurodegenerative Diseases (DZNE)RostockGermany
  11. 11.Department of NeuropathologyUniversity of TübingenTübingenGermany
  12. 12.Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  13. 13.Department of NeurologyRostock University Medical CenterRostockGermany
  14. 14.German Center for Neurodegenerative Diseases (DZNE)MunichGermany
  15. 15.Munich Cluster of Systems Neurology (SyNergy)MunichGermany
  16. 16.Center for Neuropathology and Prion ResearchLudwig-Maximilians-University of MunichMunichGermany
  17. 17.Department of Psychiatry and PsychotherapyTechnische Universität MünchenMunichGermany
  18. 18.Division of NeuropathologyUniversity of Texas Southwestern Medical CenterDallasUSA
  19. 19.London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK
  20. 20.Department of Clinical NeuropathologyKing’s College Hospital NHS Foundation TrustLondonUK
  21. 21.Mesulam Center for Cognitive Neurology and Alzheimer’s DiseaseNorthwestern UniversityChicagoUSA
  22. 22.Department of Psychiatry and Behavioral Sciences and Department of NeurologyNorthwestern University Feinberg School of MedicineChicagoUSA
  23. 23.Glenn Biggs Institute for Alzheimer’s and Neurodegenerative DiseasesUniversity of Texas Health Science Center San AntonioSan AntonioUSA
  24. 24.Department of NeurologyUniversity of Arizona Health Sciences CenterTucsonUSA
  25. 25.Banner Alzheimer’s InstitutePhoenixUSA
  26. 26.Department of NeurologyMayo Clinic ArizonaScottsdaleUSA
  27. 27.Departments of Psychiatry and Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging BrainColumbia UniversityNew YorkUSA
  28. 28.Indiana University School of MedicineIndianapolisUSA
  29. 29.Department of Physical Medicine and Rehabilitation, Neurology, Cognitive Neurology and Alzheimer’s Center, Department of Psychiatry, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  30. 30.MRC Prion Unit at University College LondonInstitute of Prion DiseasesLondonUK
  31. 31.Department of Pathology, Memory and Aging CenterUniversity of CaliforniaSan FranciscoUSA
  32. 32.Penn Frontotemporal Degeneration Center, Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  33. 33.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  34. 34.Cerebral Function Unit, Greater Manchester Neurosciences CentreSalford Royal HospitalSalfordUK
  35. 35.Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and HealthUniversity of Manchester, Salford Royal HospitalSalfordUK
  36. 36.Department of NeurologyMayo ClinicJacksonvilleUSA
  37. 37.Department of NeurologyMayo ClinicRochesterUSA
  38. 38.Central Clinical School and Brain and Mind CentreThe University of SydneySydneyAustralia
  39. 39.School of Psychology and Brain and Mind CentreThe University of SydneySydneyAustralia
  40. 40.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  41. 41.Veterans Affairs San Diego Healthcare SystemSan DiegoUSA
  42. 42.Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative DiseaseUniversity of TorontoTorontoCanada
  43. 43.Sunnybrook Health Sciences CentreTorontoCanada
  44. 44.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  45. 45.Krembil Neuroscience Center, Movement Disorder’s ClinicToronto Western HospitalTorontoCanada
  46. 46.Department of Neurology, Knight Alzheimer Disease Research CenterWashington University School of MedicineSaint LouisUSA
  47. 47.Department of Psychiatry, Knight Alzheimer Disease Research CenterWashington University School of MedicineSaint LouisUSA
  48. 48.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  49. 49.Department of PathologyUniversity of PittsburghPittsburghUSA
  50. 50.Department of NeurologyUniversity of PittsburghPittsburghUSA
  51. 51.Civin Laboratory for NeuropathologyBanner Sun Health Research InstituteSun CityUSA
  52. 52.Department of Psychiatry and Psychotherapy, University HospitalLudwig-Maximilians-University of MunichMunichGermany
  53. 53.Department of Neurology, Taub Institute, and GH Sergievsky CenterColumbia University Irving Medical CenterNew YorkUSA
  54. 54.Department of Pathology and Taub InstituteColumbia University Irving Medical CenterNew YorkUSA
  55. 55.UNSW Medicine and NeuRARandwickAustralia
  56. 56.Department of Pathology and Laboratory Medicine and Department of NeurologyEmory UniversityAtlantaUSA
  57. 57.Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and HealthUniversity of ManchesterManchesterUK
  58. 58.Dementia Research Centre, Department of Neurodegenerative DiseaseUCL Queen Square Institute of NeurologyLondonUK
  59. 59.Department of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouverCanada

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