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Acta Neuropathol. 2019 Feb 9. doi: 10.1007/s00401-019-01962-9. [Epub ahead of print]

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.

Author information

1
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
2
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
3
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
4
Department of Neurology, Erasmus Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
5
Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
6
Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
7
Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 2E2, Canada.
8
Division of Neurogeriatrics, Department NVS, Karolinska Institutet, Visionsgatan 4, J10:20, 171 64, Solna, Sweden.
9
Theme Aging, Unit for Hereditary Dementias, Karolinska University Hospital, Solna, Sweden.
10
German Center for Neurodegenerative Diseases (DZNE), 18147, Rostock, Germany.
11
Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany.
12
Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
13
Department of Neurology, Rostock University Medical Center, 18147, Rostock, Germany.
14
German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Str 17, 81377, Munich, Germany.
15
Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Str 17, 81377, Munich, Germany.
16
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Straße 23, 81377, Munich, Germany.
17
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
18
Division of Neuropathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-9073, USA.
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.
20
Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, SE5 9RS, UK.
21
Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University, Chicago, IL, 60611, USA.
22
Department of Psychiatry and Behavioral Sciences and Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
23
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, 78229, USA.
24
Department of Neurology, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ, 85724-5023, USA.
25
Banner Alzheimer's Institute, Phoenix, AZ, 85006, USA.
26
Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
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.
28
Indiana University School of Medicine, 355 West 16th Street, GH 4700 Neurology, Indianapolis, IN, 46202, USA.
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.
30
MRC Prion Unit at University College London, Institute of Prion Diseases, London, UK.
31
Department of Pathology, Memory and Aging Center, University of California, San Francisco, CA, USA.
32
Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
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.
34
Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford, UK.
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.
36
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
37
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
38
Central Clinical School and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
39
School of Psychology and Brain and Mind Centre, The University of Sydney, Sydney, 2050, Australia.
40
Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
41
Veterans Affairs San Diego Healthcare System, San Diego, CA, 92161, USA.
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.
43
Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, Canada.
44
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A1, Canada.
45
Krembil Neuroscience Center, Movement Disorder's Clinic, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada.
46
Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA.
47
Department of Psychiatry, Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, 63108, USA.
48
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Drive, MS A138, Indianapolis, IN, 46202, USA.
49
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
50
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
51
Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, 85351, USA.
52
Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University of Munich, Nussbaumstraße 7, 80336, Munich, Germany.
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.
54
Department of Pathology and Taub Institute, Columbia University Irving Medical Center, 630 West 168th St, New York, NY, 10032, USA.
55
UNSW Medicine and NeuRA, Randwick, 2031, Australia.
56
Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, 30322, USA.
57
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
58
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
59
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.
60
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Rademakers.rosa@mayo.edu.

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

PMID:
30739198
DOI:
10.1007/s00401-019-01962-9

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