. 2019 Jun;137(6):879-899.

doi: 10.1007/s00401-019-01962-9. Epub 2019 Feb 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

Cyril Pottier¹, Yingxue Ren², Ralph B Perkerson 3rd¹, Matt Baker¹, Gregory D Jenkins³, Marka van Blitterswijk¹, Mariely DeJesus-Hernandez¹, Jeroen G J van Rooij⁴, Melissa E Murray¹, Elizabeth Christopher¹, Shannon K McDonnell³, Zachary Fogarty³, Anthony Batzler³, Shulan Tian³, Cristina T Vicente¹, Billie Matchett¹, Anna M Karydas⁵, Ging-Yuek Robin Hsiung⁶, Harro Seelaar⁴, Merel O Mol⁴, Elizabeth C Finger⁷, 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 Rizzu¹⁰, Javier Simon-Sanchez^{10

12}, Dieter Edbauer^{14

15}, Sigrun Roeber¹⁶, Janine Diehl-Schmid¹⁷, Bret M Evers¹⁸, Andrew King^{19

20}, M Marsel Mesulam²¹, Sandra Weintraub^{21

22}, Changiz Geula²¹, Kevin F Bieniek^{1

23}, Leonard Petrucelli¹, Geoffrey L Ahern²⁴, Eric M Reiman²⁵, Bryan K Woodruff²⁶, Richard J Caselli²⁶, Edward D Huey²⁷, Martin R Farlow²⁸, Jordan Grafman²⁹, Simon Mead³⁰, Lea T Grinberg^{5

31}, Salvatore Spina⁵, Murray Grossman³², David J Irwin³², Edward B Lee³³, EunRan Suh³³, Julie Snowden³⁴, David Mann³⁵, Nilufer Ertekin-Taner^{1

36}, Ryan J Uitti³⁶, Zbigniew K Wszolek³⁶, Keith A Josephs³⁷, Joseph E Parisi³⁷, David S Knopman³⁷, Ronald C Petersen³⁷, John R Hodges³⁸, Olivier Piguet³⁹, Ethan G Geier⁵, Jennifer S Yokoyama⁵, Robert A Rissman^{40

41}, Ekaterina Rogaeva⁴², Julia Keith^{43

44}, Lorne Zinman⁴³, Maria Carmela Tartaglia^{42

45}, Nigel J Cairns⁴⁶, Carlos Cruchaga⁴⁷, Bernardino Ghetti⁴⁸, Julia Kofler⁴⁹, Oscar L Lopez^{24

50}, Thomas G Beach⁵¹, Thomas Arzberger^{14

16

52}, Jochen Herms^{14

16}, Lawrence S Honig⁵³, Jean Paul Vonsattel⁵⁴, Glenda M Halliday^{38

55}, John B Kwok^{38

55}, Charles L White 3rd¹⁸, Marla Gearing⁵⁶, Jonathan Glass⁵⁶, Sara Rollinson⁵⁷, Stuart Pickering-Brown⁵⁷, Jonathan D Rohrer⁵⁸, John Q Trojanowski³³, Vivianna Van Deerlin³³, Eileen H Bigio²¹, Claire Troakes¹⁹, Safa Al-Sarraj^{19

20}, Yan Asmann², Bruce L Miller⁵, Neill R Graff-Radford³⁶, Bradley F Boeve³⁷, William W Seeley^{5

31}, Ian R A Mackenzie⁵⁹, John C van Swieten⁴, Dennis W Dickson¹, Joanna M Biernacka³, Rosa Rademakers⁶⁰

Affiliations

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.

PMID: 30739198
PMCID: PMC6533145
DOI: 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

Cyril Pottier et al. Acta Neuropathol. 2019 Jun.

. 2019 Jun;137(6):879-899.

doi: 10.1007/s00401-019-01962-9. Epub 2019 Feb 9.

Authors

Affiliations

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.

PMID: 30739198
PMCID: PMC6533145
DOI: 10.1007/s00401-019-01962-9

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.

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Figures

**Figure 1.. Age distributions in each FTLD-TDP pathological subtype**
Age at onset, age at death and survival after onset are represented as histogram per FTLD-TDP pathological subtype. A density curve is superimposed to the histograms.

**Figure 2.. Common variant whole genome sequencing association study and *DPP6* locus**
(a) Manhattan plot of the FTLD-TDP patients versus control association study. The red dotted line represents the genome-wide significance level (p=5e-08). (b)Regional association (locus zoom) plot of the DPP6 locus. Each dot represents a genotyped variant. The purple dot is the most significant variant (rs4726389) among variants in the region. Dots are colored from red to blue according to their r2 value, showing their degree of linkage disequilibrium with rs4726389 (grey indicates an r2 of zero). The light blue line shows the estimated recombination rate. (c) *DPP6* mRNA expression levels in function of the rs4726389 genotypes without correction for cellular composition in custom RNAseq frontal cortex dataset. (d) *DPP6* mRNA expression levels in function of the rs4726389 genotypes with correction for cellular composition in custom RNAseq frontal cortex dataset. (e) Differential *DPP6* mRNA expression levels in FTLD-TDP patients and controls without correction for cellular composition. (f) Differential *DPP6* mRNA expression levels in FTLD-TDP patients and controls with correction for cellular composition.

See this image and copyright information in PMC

Comment in

Genetic risk factors and role of immune dysfunction in FTLD.
Galimberti D. Galimberti D. Nat Rev Neurol. 2019 May;15(5):250-251. doi: 10.1038/s41582-019-0173-5. Nat Rev Neurol. 2019. PMID: 30914791 No abstract available.

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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

Affiliations

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

Authors

Affiliations

Abstract

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Comment in

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