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).
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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
Keywords
- Whole-genome sequencing FTLD-TDP
- TBK1
- DPP6
- UNC13A
- HLA
- Immunity