Journal
ACTA NEUROPATHOLOGICA
Volume 127, Issue 3, Pages 407-418Publisher
SPRINGER
DOI: 10.1007/s00401-013-1239-x
Keywords
TMEM106B; C9orf72; Frontotemporal dementia; Frontotemporal lobar degeneration; Amyotrophic lateral sclerosis; Genetic modifier
Categories
Funding
- NIH [AG033101, NS082265, P50 AG005133]
- Neurological Tissue Bank of the Biobanc-HC-IDIBAPS [BG2010.02]
- Alzheimer Nederland/NIBC [056-13-018]
- Stichting Dioraphte [0802100]
- National Institute for Health Research
- SOPHIA
- EuroMotor
- National Health and Medical Research Council of Australia (NHMRC) (FTLD)
- NHMRC [1037746]
- Neuroscience Research Australia, University of New South Wales
- MetLife Foundation, USA
- Interuniversity Attraction Poles program of the Belgian Science Policy Office (BELSPO)
- Europe Initiative on Centers of Excellence in Neurodegeneration (CoEN)
- Methusalem program supported by the Flemish Government
- Foundation Alzheimer Research (SAO/FRA)
- Medical Foundation Queen Elisabeth
- Research Foundation Flanders (FWO)
- Agency for Innovation by Science and Technology Flanders (IWT)
- University of Antwerp Research Fund, Belgium
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Doris Duke Clinician Scientist Development Award
- Benaroya Fund
- Glenda Halliday holds a NHMRC Senior Principal Research Fellowship
- NIHR Queen Square Dementia Biomedical Research unit
- UCL Institute of Neurology Dementia Research Centre
- Alzheimer's Research UK
- Brain Research Trust
- Wolfson Foundation
- MRC [MR/K003771/1, G0800380, MC_U123160651, MR/K000039/1] Funding Source: UKRI
- Medical Research Council [MR/K006584/1, MC_U123160651, MR/K000039/1, MR/K003771/1, G0800380] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10123, NF-SI-0512-10082, CL-2012-18-010, NF-SI-0512-10033, NF-SI-0513-10134] Funding Source: researchfish
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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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