Publication:
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexnucleotide repeat expansion
TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexnucleotide repeat expansion
dc.contributor.author | Gallagher, Michael D | en_US |
dc.contributor.author | Suh, Eunran | en_US |
dc.contributor.author | Grossman, Murray | en_US |
dc.contributor.author | Elman, Lauren | en_US |
dc.contributor.author | McCluskey, Leo | en_US |
dc.contributor.author | Van Swieten, John C | en_US |
dc.contributor.author | Al-Sarraj, Safa | en_US |
dc.contributor.author | Neumann, Manuela | en_US |
dc.contributor.author | Gelpi, Ellen | en_US |
dc.contributor.author | Rohrer, Jonathan D | en_US |
dc.contributor.author | Halliday, Glenda | en_US |
dc.contributor.author | Ghetti, Bernardino | en_US |
dc.contributor.author | Van Broeckhoven, Christine | en_US |
dc.contributor.author | Seilhean, Danielle | en_US |
dc.contributor.author | Shaw, Pamela J | en_US |
dc.contributor.author | Frosch, Matthew P | en_US |
dc.contributor.author | Trojanowski, John Q | en_US |
dc.contributor.author | Lee, Virginia MY | en_US |
dc.contributor.author | Van Deerlin, Vivianna | en_US |
dc.contributor.author | Chen-Plotkin, Alice S | en_US |
dc.date.accessioned | 2021-11-25T12:29:03Z | |
dc.date.available | 2021-11-25T12:29:03Z | |
dc.date.issued | 2014 | en_US |
dc.description.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 (ALS), 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 43kDa (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. | en_US |
dc.identifier.issn | 0001-6322 | en_US |
dc.identifier.uri | http://hdl.handle.net/1959.4/53586 | |
dc.language | English | |
dc.language.iso | EN | en_US |
dc.rights | CC BY-NC-ND 3.0 | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/au/ | en_US |
dc.source | Legacy MARC | en_US |
dc.subject.other | fFrontotemporal dementia | en_US |
dc.subject.other | TMEM106B | en_US |
dc.subject.other | C9orf72 | en_US |
dc.subject.other | Frontotemporal lobar degeneration | en_US |
dc.subject.other | Amyotrophic lateral sclerosis | en_US |
dc.subject.other | Genetic modifier | en_US |
dc.title | TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexnucleotide repeat expansion | en_US |
dc.type | Journal Article | en |
dcterms.accessRights | open access | |
dspace.entity.type | Publication | en_US |
unsw.accessRights.uri | https://purl.org/coar/access_right/c_abf2 | |
unsw.description.publisherStatement | The final publication is available at Springer via http://dx.doi.org/10.1007/s00401-013-1239-x | en_US |
unsw.identifier.doiPublisher | http://dx.doi.org/10.1007/s00401-013-1239-x | en_US |
unsw.relation.faculty | Medicine & Health | |
unsw.relation.ispartofissue | 3 | en_US |
unsw.relation.ispartofjournal | Acta Neuropathologica | en_US |
unsw.relation.ispartofpagefrompageto | 407-418 | en_US |
unsw.relation.ispartofvolume | 127 | en_US |
unsw.relation.originalPublicationAffiliation | Gallagher, Michael D, School of Medicine, University of Pennsylvania, Philadelphia | en_US |
unsw.relation.originalPublicationAffiliation | Suh, Eunran, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | en_US |
unsw.relation.originalPublicationAffiliation | Grossman, Murray, Department of Neurology, Perelman School of Medicine, University of Pennsylvania | en_US |
unsw.relation.originalPublicationAffiliation | Elman, Lauren, Department of Neurology, Perelman School of Medicine, University of Pennsylvania | en_US |
unsw.relation.originalPublicationAffiliation | McCluskey, Leo, Department of Neurology, Perelman School of Medicine, University of Pennsylvania | en_US |
unsw.relation.originalPublicationAffiliation | Van Swieten, John C, Erasmus Medical Centre, s’Gravendijkwal 230, Rotterdam, The Netherlands | en_US |
unsw.relation.originalPublicationAffiliation | Al-Sarraj, Safa, King’s College Hospital, London, UK | en_US |
unsw.relation.originalPublicationAffiliation | Neumann, Manuela, University of Tübingen, Calwerstr. 3, 72072 Tübingen, Germany | en_US |
unsw.relation.originalPublicationAffiliation | Gelpi, Ellen, Neurological Tissue Bank of the Biobank-Hospital Clinic-Insitut d’Investigacions Biomèdiques August Pi i Sunyer, Facultad de Medicin | en_US |
unsw.relation.originalPublicationAffiliation | Rohrer, Jonathan D, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK | en_US |
unsw.relation.originalPublicationAffiliation | Halliday, Glenda, Neuroscience Research Australia, Faculty of Medicine, UNSW | en_US |
unsw.relation.originalPublicationAffiliation | Ghetti, Bernardino, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA | en_US |
unsw.relation.originalPublicationAffiliation | Van Broeckhoven, Christine, Neurodegenerative Brain Disease Group, Department of Molecular Genetics, VIB, Universiteitsplein 1, 2610 Antwerp, Belgium | en_US |
unsw.relation.originalPublicationAffiliation | Seilhean, Danielle, University Pierre et Marie Curie (UPMC)-Sorbonne University, Paris, France | en_US |
unsw.relation.originalPublicationAffiliation | Shaw, Pamela J, University of Sheffield, SITraN, 385a Glossop Road, Sheffield S10 2HQ, UK | en_US |
unsw.relation.originalPublicationAffiliation | Frosch, Matthew P, Massachusetts Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA, USA | en_US |
unsw.relation.originalPublicationAffiliation | Trojanowski, John Q, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | en_US |
unsw.relation.originalPublicationAffiliation | Lee, Virginia MY, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | en_US |
unsw.relation.originalPublicationAffiliation | Van Deerlin, Vivianna, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | en_US |
unsw.relation.originalPublicationAffiliation | Chen-Plotkin, Alice S, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3 W Gates, 3400 Spruce St, Philadelphia, PA 19104, USA | en_US |
unsw.relation.school | Neuroscience Research Australia | * |
unsw.subject.fieldofresearchcode | 110903 Central Nervous System | en_US |
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