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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

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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.

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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).

Author information

Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Cyril Pottier, Ralph B. Perkerson III, Matt Baker, Marka van Blitterswijk, Mariely DeJesus-Hernandez, Melissa E. Murray, Elizabeth Christopher, Cristina T. Vicente, Billie Matchett, Kevin F. Bieniek, Leonard Petrucelli, Nilufer Ertekin-Taner, Dennis W. Dickson & Rosa Rademakers

  2. Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA

    Yingxue Ren & Yan Asmann

  3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Gregory D. Jenkins, Shannon K. McDonnell, Zachary Fogarty, Anthony Batzler, Shulan Tian & Joanna M. Biernacka

  4. Department of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands

    Jeroen G. J. van Rooij, Harro Seelaar, Merel O. Mol & John C. van Swieten

  5. Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA

    Anna M. Karydas, Lea T. Grinberg, Salvatore Spina, Ethan G. Geier, Jennifer S. Yokoyama, Bruce L. Miller & William W. Seeley

  6. Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada

    Ging-Yuek Robin Hsiung

  7. Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 2E2, Canada

    Elizabeth C. Finger

  8. Division of Neurogeriatrics, Department NVS, Karolinska Institutet, Visionsgatan 4, J10:20, 171 64, Solna, Sweden

    Caroline Graff & Linn Öijerstedt

  9. Theme Aging, Unit for Hereditary Dementias, Karolinska University Hospital, Solna, Sweden

    Caroline Graff & Linn Öijerstedt

  10. German Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany

    Manuela Neumann, Peter Heutink, Matthis Synofzik, Carlo Wilke, Johannes Prudlo, Patrizia Rizzu & Javier Simon-Sanchez

  11. Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany

    Manuela Neumann

  12. Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany

    Peter Heutink, Matthis Synofzik, Carlo Wilke & Javier Simon-Sanchez

  13. Department of Neurology, Rostock University Medical Center, 18147, Rostock, Germany

    Johannes Prudlo

  14. German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str 17, 81377, Munich, Germany

    Dieter Edbauer, Thomas Arzberger & Jochen Herms

  15. Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str 17, 81377, Munich, Germany

    Dieter Edbauer

  16. Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Straße 23, 81377, Munich, Germany

    Sigrun Roeber, Thomas Arzberger & Jochen Herms

  17. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany

    Janine Diehl-Schmid

  18. Division of Neuropathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9073, USA

    Bret M. Evers & Charles L. White III

  19. London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, SE5 8AF, UK

    Andrew King, Claire Troakes & Safa Al-Sarraj

  20. Department of Clinical Neuropathology, King’s College Hospital NHS Foundation Trust, London, SE5 9RS, UK

    Andrew King & Safa Al-Sarraj

  21. Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Northwestern University, Chicago, IL, 60611, USA

    M. Marsel Mesulam, Sandra Weintraub, Changiz Geula & Eileen H. Bigio

  22. Department of Psychiatry and Behavioral Sciences and Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Sandra Weintraub

  23. Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA

    Kevin F. Bieniek

  24. Department of Neurology, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ, 85724-5023, USA

    Geoffrey L. Ahern & Oscar L. Lopez

  25. Banner Alzheimer’s Institute, Phoenix, AZ, 85006, USA

    Eric M. Reiman

  26. Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA

    Bryan K. Woodruff & Richard J. Caselli

  27. Departments of Psychiatry and Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, 630 West 168th St P&S Box 16, New York, NY, 10032, USA

    Edward D. Huey

  28. Indiana University School of Medicine, 355 West 16th Street, GH 4700 Neurology, Indianapolis, IN, 46202, USA

    Martin R. Farlow

  29. Department of Physical Medicine and Rehabilitation, Neurology, Cognitive Neurology and Alzheimer’s Center, Department of Psychiatry, Feinberg School of Medicine, Northwestern University, 355 E Erie Street, Chicago, IL, 60611-5146, USA

    Jordan Grafman

  30. MRC Prion Unit at University College London, Institute of Prion Diseases, London, UK

    Simon Mead

  31. Department of Pathology, Memory and Aging Center, University of California, San Francisco, CA, USA

    Lea T. Grinberg & William W. Seeley

  32. Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Murray Grossman & David J. Irwin

  33. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Edward B. Lee, EunRan Suh, John Q. Trojanowski & Vivianna Van Deerlin

  34. Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford, UK

    Julie Snowden

  35. Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, UK

    David Mann

  36. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Nilufer Ertekin-Taner, Ryan J. Uitti, Zbigniew K. Wszolek & Neill R. Graff-Radford

  37. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen & Bradley F. Boeve

  38. Central Clinical School and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia

    John R. Hodges, Glenda M. Halliday & John B. Kwok

  39. School of Psychology and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia

    Olivier Piguet

  40. Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA

    Robert A. Rissman

  41. Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA

    Robert A. Rissman

  42. Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, 60 Leonard Av, 4th Floor - 4KD481, Toronto, ON, M5T 0S8, Canada

    Ekaterina Rogaeva & Maria Carmela Tartaglia

  43. Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada

    Julia Keith & Lorne Zinman

  44. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Julia Keith

  45. Krembil Neuroscience Center, Movement Disorder’s Clinic, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada

    Maria Carmela Tartaglia

  46. Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA

    Nigel J. Cairns

  47. Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA

    Carlos Cruchaga

  48. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MS A138, Indianapolis, IN, 46202, USA

    Bernardino Ghetti

  49. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Julia Kofler

  50. Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Oscar L. Lopez

  51. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, 85351, USA

    Thomas G. Beach

  52. Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University of Munich, Nussbaumstraße 7, 80336, Munich, Germany

    Thomas Arzberger

  53. Department of Neurology, Taub Institute, and GH Sergievsky Center, Columbia University Irving Medical Center, 630 West 168th St (P&S Unit 16), New York, NY, 10032, USA

    Lawrence S. Honig

  54. Department of Pathology and Taub Institute, Columbia University Irving Medical Center, 630 West 168th St, New York, NY, 10032, USA

    Jean Paul Vonsattel

  55. UNSW Medicine and NeuRA, Randwick, 2031, Australia

    Glenda M. Halliday & John B. Kwok

  56. Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, 30322, USA

    Marla Gearing & Jonathan Glass

  57. Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Sara Rollinson & Stuart Pickering-Brown

  58. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK

    Jonathan D. Rohrer

  59. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada

    Ian R. A. Mackenzie

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  1. Cyril Pottier
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Corresponding author

Correspondence to Rosa Rademakers.

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Pottier, C., Ren, Y., Perkerson, R.B. et al. 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 Neuropathol 137, 879–899 (2019). https://doi.org/10.1007/s00401-019-01962-9

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  • DOI: https://doi.org/10.1007/s00401-019-01962-9

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