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Lancet Neurol. 2018 Jun;17(6):548-558. doi: 10.1016/S1474-4422(18)30126-1. Epub 2018 Apr 30.

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

Pottier C1, Zhou X1, Perkerson RB 3rd1, Baker M1, Jenkins GD2, Serie DJ3, Ghidoni R4, Benussi L4, Binetti G5, López de Munain A6, Zulaica M7, Moreno F6, Le Ber I8, Pasquier F9, Hannequin D10, Sánchez-Valle R11, Antonell A11, Lladó A11, Parsons TM1, Finch NA1, Finger EC12, Lippa CF13, Huey ED14, Neumann M15, Heutink P16, Synofzik M16, Wilke C16, Rissman RA17, Slawek J18, Sitek E18, Johannsen P19, Nielsen JE19, Ren Y3, van Blitterswijk M1, DeJesus-Hernandez M1, Christopher E1, Murray ME1, Bieniek KF1, Evers BM20, Ferrari C21, Rollinson S22, Richardson A23, Scarpini E24, Fumagalli GG25, Padovani A26, Hardy J27, Momeni P28, Ferrari R27, Frangipane F29, Maletta R29, Anfossi M29, Gallo M29, Petrucelli L1, Suh E30, Lopez OL31, Wong TH32, van Rooij JGJ32, Seelaar H32, Mead S33, Caselli RJ34, Reiman EM35, Noel Sabbagh M36, Kjolby M37, Nykjaer A37, Karydas AM38, Boxer AL38, Grinberg LT39, Grafman J40, Spina S41, Oblak A42, Mesulam MM43, Weintraub S44, Geula C43, Hodges JR45, Piguet O46, Brooks WS47, Irwin DJ48, Trojanowski JQ30, Lee EB30, Josephs KA49, Parisi JE49, Ertekin-Taner N50, Knopman DS49, Nacmias B51, Piaceri I51, Bagnoli S51, Sorbi S52, Gearing M53, Glass J53, Beach TG54, Black SE55, Masellis M55, Rogaeva E56, Vonsattel JP57, Honig LS58, Kofler J59, Bruni AC29, Snowden J23, Mann D60, Pickering-Brown S22, Diehl-Schmid J61, Winkelmann J62, Galimberti D24, Graff C63, Öijerstedt L63, Troakes C64, Al-Sarraj S65, Cruchaga C66, Cairns NJ67, Rohrer JD68, Halliday GM45, Kwok JB69, van Swieten JC70, White CL 3rd20, Ghetti B42, Murell JR42, Mackenzie IRA71, Hsiung GR72, Borroni B26, Rossi G73, Tagliavini F74, Wszolek ZK75, Petersen RC49, Bigio EH43, Grossman M48, Van Deerlin VM30, Seeley WW39, Miller BL38, Graff-Radford NR75, Boeve BF49, Dickson DW1, Biernacka JM2, Rademakers R76.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
2
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
3
Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
4
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
5
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy; MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
6
Biodonostia Health Research Institute-CIBERNED-UPV-EHU, San Sebastian, Spain; Department of Neurology, Hospital Universitario Donostia, UPV/EHU, San Sebastian, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases, Institute of Health Carlos III, ISCIII, San Sebastian, Spain.
7
Biodonostia Health Research Institute-CIBERNED-UPV-EHU, San Sebastian, Spain; Center for Networked Biomedical Research on Neurodegenerative Diseases, Institute of Health Carlos III, ISCIII, San Sebastian, Spain.
8
Department of Neurology, Reference Center for Rare and Young Dementias, Institute of Memory and Alzheimer's Disease (IM2A), Hopital Pitié-Salpêtrière, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière (ICM), Hopital Pitié-Salpêtrière, Paris, France.
9
University of Lille, INSERM U1171, CHU, National Reference Center for Young Onset Dementia, DISTALZ, Lille, France.
10
Centre National de Référence pour les Malades Alzheimer Jeunes, CNR-MAJ, INSERM 1245, Centre Hospitalier Universitaire de Rouen, Rouen, France.
11
Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain.
12
Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
13
Cognitive Disorders and Comprehensive Alzheimer's Disease Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA.
14
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
15
German Center for Neurodegenerative Diseases (DZNE), Molecular Neuropathology of Neurodegenerative Diseases, Tübingen, Germany; Department of Neuropathology, University of Tübingen, Tübingen, Germany.
16
Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center for Neurology, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Genome Biology of Neurodegenerative Diseases, Tübingen, Germany.
17
Veterans Affairs San Diego Healthcare System San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
18
Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Gdansk, Poland.
19
Department of Neurology, Rigshospitalet, Danish Dementia Research Centre, University of Copenhagen, Copenhagen, Denmark.
20
Division of Neuropathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
21
IRCCS Don Gnocchi, Florence, Italy.
22
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
23
Cerebral Function Unit, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Salford, UK.
24
Department of Pathophysiology and Transplantation, Neurodegenerative Disease Unit, University of Milan, Centro Dino Ferrari, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
25
Department of Pathophysiology and Transplantation, Neurodegenerative Disease Unit, University of Milan, Centro Dino Ferrari, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
26
Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.
27
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
28
Rona Holdings, Silicon Valley, CA, USA.
29
Regional Neurogenetic Centre, ASP Catanzaro, Lamezia Terme, Italy.
30
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.
31
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
32
Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands.
33
MCR Prion Unit at UCL, Institute of Prion Diseases, London, UK.
34
Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.
35
Banner Alzheimer's Institute, Phoenix, AZ, USA.
36
Barrow Neurological Institute, University of Arizona College of Medicine Phoenix, Creighton University School of Medicine, Phoenix, AZ, USA.
37
Department of Biomedicine, The Lundbeck Foundation Research Center MIND, The Danish National Research Foundation Center of Excellence PROMEMO, DANDRITE, Aarhus University, and Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.
38
Department of Neurology, University of California, Memory and Aging Center, San Francisco, CA, USA.
39
Department of Neurology, University of California, Memory and Aging Center, San Francisco, CA, USA; Department of Pathology, University of California, Memory and Aging Center, San Francisco, CA, USA.
40
Shirley Ryan AbilityLab and Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
41
University of California Memory and Aging Center, San Francisco, CA, USA; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
42
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
43
Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Chicago, IL, USA.
44
Cognitive Neurology and Alzheimer Disease Center, Northwestern University, Chicago, IL, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA; Department of Neurosciences Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
45
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
46
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia; School of Psychology, University of Sydney, Sydney, NSW, Australia.
47
Neuroscience Research Australia, University of Sydney, Sydney, NSW, Australia; University of New South Wales, Sydney, NSW, Australia.
48
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, USA.
49
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
50
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
51
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
52
IRCCS Don Gnocchi, Florence, Italy; Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
53
Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University, Atlanta, GA, USA.
54
Banner Sun Health Research Institute, Civin Laboratory for Neuropathology, Sun City, AZ, USA.
55
Department of Medicine (Neurology), University of Toronto and Sunnybrook Health Sciences Centre, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada.
56
Department of Medicine Neurology, University of Toronto, Tanz Centre for Research in Neurodegenerative Disease, Toronto, ON, Canada.
57
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Department of Pathology, Columbia University Medical Center, New York, NY, USA.
58
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA; Department of Neurology, Columbia University Medical Center, New York, NY, USA.
59
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
60
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Salford Royal Hospital, Salford, UK.
61
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
62
Institute of Neurogenomics, Helmholtz Zentrum München, Neurologische Klinik und Poliklinik und Institut für Humangenetik, Klinikum rechts der Isar, Technical University of Munich, Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.
63
Division of Neurogeriatrics, Alzheimer Research Center, Karolinska Institutet, Solna, Sweden; Genetics Unit, Theme Aging, Karolinska University Hospital, Stockholm, Sweden.
64
Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
65
Department of Basic and Clinical Neuroscience, London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Clinical Neuropathology King's College Hospital, NHS Foundation Trust, London, UK.
66
Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, USA; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
67
Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, USA.
68
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
69
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
70
Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Neurology, VU Medical Centre, Amsterdam, Netherlands.
71
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
72
Division of Neurology, University of British Columbia, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
73
Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
74
Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
75
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
76
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: rademakers.rosa@mayo.edu.

Abstract

BACKGROUND:

Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.

METHODS:

The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10-5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin.

FINDINGS:

Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10-16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10-8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2.

INTERPRETATION:

TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals.

FUNDING:

National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

PMID:
29724592
PMCID:
PMC6237181
[Available on 2019-06-01]
DOI:
10.1016/S1474-4422(18)30126-1
[Indexed for MEDLINE]

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