TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Michael D. Gallagher, Eunran Suh, Murray Grossman, Lauren Elman, Leo McCluskey, John C. Van Swieten, Safa Al-Sarraj, Manuela Neumann, Ellen Gelpi, Bernardino Ghetti, Jonathan D. Rohrer, Glenda Halliday, Christine Van Broeckhoven, Danielle Seilhean, Pamela J. Shaw, Matthew P. Frosch, Irina Alafuzoff, Anna Antonell, Nenad Bogdanovic, William BrooksNigel J. Cairns, Johnathan Cooper-Knock, Carl 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, Päivi Hartikainen, Kimmo J. Hatanpaa, J. Robin Highley, John Hodges, Christine Hulette, Paul G. Ince, Lee Way Jin, Janine Kirby, Julia Kofler, Jillian Kril, John B J Kwok, Allan Levey, Andrew Lieberman, Albert Llado, Jean Jacques Martin, Eliezer Masliah, Christopher J. McDermott, Ann McKee, Catriona McLean, Simon Mead, Carol A. Miller, Josh Miller, David G. Munoz, Jill Murrell, Henry Paulson, Olivier Piguet, Martin Rossor, Raquel Sanchez-Valle, Mary Sano, Julie Schneider, Lisa C. Silbert, Salvatore Spina, Julie Van Der Zee, Tim Van Langenhove, Jason Warren, Stephen B. Wharton, Charles L. White, Randall L. Woltjer, John Q. Trojanowski, Virginia M Y Lee, Vivianna Van Deerlin, Alice S. Chen-Plotkin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)407-418
Number of pages12
JournalActa Neuropathologica
Volume127
Issue number3
DOIs
StatePublished - Mar 2014

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Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Genetic modifier
  • TMEM106B

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Gallagher, M. D., Suh, E., Grossman, M., Elman, L., McCluskey, L., Van Swieten, J. C., Al-Sarraj, S., Neumann, M., Gelpi, E., Ghetti, B., Rohrer, J. D., Halliday, G., Van Broeckhoven, C., Seilhean, D., Shaw, P. J., Frosch, M. P., Alafuzoff, I., Antonell, A., Bogdanovic, N., ... Chen-Plotkin, A. S. (2014). TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathologica, 127(3), 407-418. https://doi.org/10.1007/s00401-013-1239-x