Abstract
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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Acknowledgments
Contributing sites that provided C9orf72 genetic data included Erasmus University, Rotterdam, The Netherlands; Indiana University, Indianapolis, Indiana; Banc de Teixits Neurologics-Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain; Kings College, London, UK; UCL Institute of Neurology, Queen Square, London, UK; Ludwig-Maximilians University, Munich, Germany; University of New South Wales, Sydney, Australia; VIB, University of Antwerp, Antwerp, Belgium; Massachusetts General Hospital, Boston, Massachusetts; University of Sheffield, Sheffield, UK; Institut National de la Santé et de la Recherche Laboratoire de Neuropathologie, Paris, France. Contributing sites with C9orf72(+) cases identified at UPenn included: Sydney Brain Bank, Australia; Boston University, Boston, Massachusetts; Duke University, Durham, North Carolina; Emory University, Atlanta; Georgia; Karolinska Institute, Stockholm, Sweden; Mt. Sinai School of Medicine, Bronx, New York; Oregon Health Sciences University, Portland, Oregon; University of Pittsburgh, Pittsburgh, Pennsylvania; Rush University, Chicago, Illinois; University of Texas Southwestern, Dallas, Texas; University of Toronto, Toronto, Canada; University of California (Davis, Irvine, San Diego campuses), California; University of Michigan, Ann Arbor, Michigan; University of Kuopio, Finland; University of Southern California, Los Angeles, California; Washington University, St. Louis, Missouri; University of Pennsylvania, Philadelphia, Pennsylvania.
Sources of support for this project include the NIH (AG033101, NS082265, P50 AG005133), The Neurological Tissue Bank of the Biobanc-HC-IDIBAPS, Hersenstichting project BG2010.02, Alzheimer Nederland/NIBC 056-13-018, Stichting Dioraphte projectnr 0802100, The National Institute for Health Research, SOPHIA, EuroMotor, National Health and Medical Research Council of Australia (NHMRC) (FTLD cases supported by NHMRC program grant 1037746), and Neuroscience Research Australia, University of New South Wales. The Antwerp site is in part funded by the MetLife Foundation, USA; the Interuniversity Attraction Poles program of the Belgian Science Policy Office (BELSPO), the Europe Initiative on Centers of Excellence in Neurodegeneration (CoEN) and the Methusalem program supported by the Flemish Government; the Foundation Alzheimer Research (SAO/FRA); the Medical Foundation Queen Elisabeth; the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology Flanders (IWT), the University of Antwerp Research Fund, Belgium. The FWO provided a postdoctoral fellowship to J.v.d.Z and I.G. Alice Chen-Plotkin is also supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, a Doris Duke Clinician Scientist Development Award, and the Benaroya Fund. Glenda Halliday holds a NHMRC Senior Principal Research Fellowship. Jonathan D. Rohrer and Martin Rosser are supported by the NIHR Queen Square Dementia Biomedical Research unit and work at the UCL Institute of Neurology Dementia Research Centre which is supported by Alzheimer’s Research UK, Brain Research Trust, and The Wolfson Foundation.
We thank Travis Unger and Beth McCarty Wood for technical assistance. We thank our patients and their families for their participation in this research.
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The International Collaboration for Frontotemporal Lobar Degeneration consisted of clinical sites collaborating to collect cases for an FTLD-TDP genome-wide association study (GWAS); this GWAS led to the discovery that common variants in TMEM106B are a genetic risk factor for FTLD-TDP [38]. Members of the Collaboration who contributed C9orf72(+)FTLD-TDP cases for the current study include Irina Alafuzoff, Anna Antonell, Nenad Bogdanovic, William Brooks, Nigel Cairns, Johnathan Cooper-Knock, Carl W. Cotman, Patrick Cras, Marc Cruts, Peter P. De Deyn, Charles DeCarli, Carol Dobson-Stone, Sebastiaan Engelborghs, Nick Fox, Douglas Galasko, Marla Gearing, Ilse Gijselinck, Jordan Grafman, Paivi Hartikainen, Kimmo J. Hatanpaa, J. Robin Highley, John Hodges, Christine Hulette, Paul G. Ince, Lee-Way Jin, Janine Kirby, Julia Kofler, Jillian Kril, John J. B. Kwok, Allan Levey, Andrew Lieberman, Albert Llado, Jean-Jacques Martin, Eliezer Masliah, Christopher J. McDermott, Catriona McLean, Ann C. McKee, Simon Mead, Carol A. Miller, Josh Miller, David Munoz, Jill Murrell, Henry Paulson, Olivier Piguet, Martin Rossor, Raquel Sanchez-Valle, Mary Sano, Julie Schneider, Lisa Silbert, Salvatore Spina, Julie van der Zee, Tim Van Langenhove, Jason Warren, Stephen B. Wharton, Charles L. White III, Randall Woltjer.
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Gallagher, M.D., Suh, E., Grossman, M. et al. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 127, 407–418 (2014). https://doi.org/10.1007/s00401-013-1239-x
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DOI: https://doi.org/10.1007/s00401-013-1239-x