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Brain. 2018 Oct 1;141(10):2895-2907. doi: 10.1093/brain/awy238.

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Collaborators (155)

Ferrari R, Hernandez DG, Nalls MA, Rohrer JD, Ramasamy A, Kwok JBJ, Dobson-Stone C, Brooks WS, Schofield PR, Halliday GM, Hodges JR, Piguet O, Bartley L, Thompson E, Hernández I, Ruiz A, Boada M, Borroni B, Padovani A, Cruchaga C, Cairns NJ, Benussi L, Binetti G, Ghidoni R, Forloni G, Albani D, Galimberti D, Fenoglio C, Serpente M, Scarpini E, Clarimón J, Lleó A, Blesa R, Wald Ouml ML, Nilsson K, Nilsson C, Mackenzie IRA, Hsiung GR, Mann DMA, Grafman J, Morris CM, Attems J, Griffiths TD, McKeith IG, Thomas AJ, Pietrini P, Huey ED, Wassermann EM, Baborie A, Jaros E, Tierney MC, Pastor P, Razquin C, Ortega-Cubero S, Alonso E, Perneczky R, Diehl-Schmid J, Alexopoulos P, Kurz A, Rainero I, Rubino E, Pinessi L, Rogaeva E, St George-Hyslop P, Rossi G, Tagliavini F, Giaccone G, Rowe JB, Schlachetzki JCM, Uphill J, Collinge J, Mead S, Danek A, Van Deerlin VM, Grossman M, Trojanowski JQ, van der Zee J, Van Broeckhoven C, Cappa SF, Leber I, Hannequin D, Golfier V, Vercelletto M, Brice A, Nacmias B, Sorbi S, Bagnoli S, Piaceri I, Nielsen JE, Hjermind LE, Riemenschneider M, Mayhaus M, Ibach B, Gasparoni G, Pichler S, Gu W, Rossor MN, Fox NC, Warren JD, Grazia Spillantini M, Morris HR, Rizzu P, Heutink P, Snowden JS, Rollinson S, Richardson A, Gerhard A, Bruni AC, Maletta R, Frangipane F, Cupidi C, Bernardi L, Anfossi M, Gallo M, Elena Conidi M, Smirne N, Rademakers R, Baker M, Dickson DW, Graff-Radford NR, Petersen RC, Knopman D, Josephs KA, Boeve BF, Parisi JE, Seeley WW, Miller BL, Karydas AM, Rosen H, van Swieten JC, Dopper EGP, Seelaar H, Pijnenburg YAL, Scheltens P, Logroscino G, Capozzo R, Novelli V, Puca AA, Franceschi M, Postiglione A, Milan G, Sorrentino P, Kristiansen M, Chiang HH, Graff C, Pasquier F, Rollin A, Deramecourt V, Lebouvier T, Kapogiannis D, Ferrucci L, Pickering-Brown S, Singleton AB, Hardy J, Momeni P.

Author information

1
Shanghai First Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai, China.
2
Institute for Advanced Study, Tongji University, Shanghai, China.
3
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
4
Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK.
5
Krembil Neuroscience Center, University Health Network Memory clinic, Toronto Western Hospital, Toronto, ON, Canada.
6
Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada.
7
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
8
Laboratorio de Biología Molecular, Departamento de Neuropatología, Instituto de Investigaciones Neurológicas Dr. Raúl Carrea (FLENI), Buenos Aires, Argentina.
9
Baycrest Health Science, Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
10
School of Pharmacy, University of Reading, Whiteknights, Reading, UK.
11
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
12
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
13
Department of Laboratory Medicine and Pathology and Department of Neurology, Mayo Clinic, Rochester, MN, USA.
14
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
15
Department of Neurology, University of California San Francisco Memory and Aging Center, San Francisco, CA, USA.
16
Department of Neurology and Department of Pathology, University of California San Francisco Memory and Aging Center, San Francisco, CA, USA.
17
Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
18
Alzheimer Center, VU University Medical Center, Amsterdam Neuroscience, Amsterdam, The Netherlands.
19
Neurodegenerative Brain Diseases, Center of Molecular Neurology, VIB, Antwerp, Belgium.
20
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
21
Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière (ICM), Paris, France.
22
Reference Center for Rare and Young Dementias, Institute of Memory and Alzheimer's Disease (IM2A), Department of Neurology, Hopital Pitié-Salpêtrière, Paris, France.
23
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
24
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
25
MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.
26
Division of Neurogeriatrics, Alzheimer Research Center, Karolinska Institutet, Solna, Sweden.
27
Genetics Unit, Theme Aging, Karolinska University Hospital, Stockholm, Sweden.
28
Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, University of Manchester, UK.
29
Division of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
30
Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
31
Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
32
Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
33
School of Medical Sciences, University of New South Wales, Sydney, Australia.
34
Australian Research Council Centre of Excellence in Cognition and its Disorders, Sydney, Australia.
35
School of Psychology and Brain and Mind Centre, University of Sydney, Sydney, Australia.
36
MAC Memory Center, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
37
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
38
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
39
IRCCS Don Gnocchi, Florence, Italy.
40
Regional Neurogenetic Centre, Lamezia Terme, Azienda Sanitaria Provinciale Catanzaro, Italy.
41
Neurodegenerative Disease Unit, University of Milan, Fondazione Ca' Granda, IRCCS Ospedale Policlinico, Milan, Italy.
42
Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.
43
IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
44
Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
45
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.
46
Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain.
47
Fundació per la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain.
48
Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
49
National Reference Center for Young Onset Dementia, Neurology Department, Centre Hospitalier Régional Universitaire de Lille, University Hospital, Inserm U1171, DistAlz, Lille, France.
50
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
51
Department of Psychiatry and Psychotherapy, Division of Mental Health in Older Adults and Alzheimer Therapy and Research Center, Ludwig-Maximilians-Universität München, Munich, Germany.
52
Imperial College London, School of Public Health, Neuroepidemiology and Ageing Research Unit, London, UK.
53
Cognitive Neurology and Alzheimer's Center, Department of Psychiatry, Feinberg School of Medicine Chicago, IL, USA.
54
Department of Psychology, Weinberg College of Arts and Sciences Northwestern University Chicago, IL, USA.
55
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
56
The Gertrude H. Sergievsky Center, The Departments of Neurology, Psychiatry, Epidemiology, School of Public Health, Columbia University, New York, NY, USA.
57
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
58
Rona Holdings, Silicon Valley, CA, USA.
59
Merck & Co., Inc, Kenilworth, NJ, USA.

Abstract

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

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