Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions

Vivianna M. Van Deerlin, Patrick M.A. Sleiman, Maria Martinez-Lage, Alice Chen-Plotkin, Li San Wang, Neill R. Graff-Radford, Dennis W. Dickson, Rosa Rademakers, Bradley F. Boeve, Murray Grossman, Steven E. Arnold, David M.A. Mann, Stuart M. Pickering-Brown, Harro Seelaar, Peter Heutink, John C. Van Swieten, Jill R. Murrell, Bernardino Ghetti, Salvatore Spina, Jordan GrafmanJohn Hodges, Maria Grazia Spillantini, Sid Gilman, Andrew P. Lieberman, Jeffrey A. Kaye, Randall L. Woltjer, Eileen H. Bigio, Marsel Mesulam, Safa Al-Sarraj, Claire Troakes, Roger N. Rosenberg, Charles L. White, Isidro Ferrer, Albert Lladó, Manuela Neumann, Hans A. Kretzschmar, Christine Marie Hulette, Kathleen A. Welsh-Bohmer, Bruce L. Miller, Ainhoa Alzualde, Adolfo Lopez De Munain, Ann C. McKee, Marla Gearing, Allan I. Levey, James J. Lah, John Hardy, Jonathan D. Rohrer, Tammaryn Lashley, Ian R.A. MacKenzie, Howard H. Feldman, Ronald L. Hamilton, Steven T. Dekosky, Julie Van Der Zee, Samir Kumar-Singh, Christine Van Broeckhoven, Richard Mayeux, Jean Paul G. Vonsattel, Juan C. Troncoso, Jillian J. Kril, John B.J. Kwok, Glenda M. Halliday, Thomas D. Bird, Paul G. Ince, Pamela J. Shaw, Nigel J. Cairns, John C. Morris, Catriona Ann McLean, Charles Decarli, William G. Ellis, Stefanie H. Freeman, Matthew P. Frosch, John H. Growdon, Daniel P. Perl, Mary Sano, David A. Bennett, Julie A. Schneider, Thomas G. Beach, Eric M. Reiman, Bryan K. Woodruff, Jeffrey Cummings, Harry V. Vinters, Carol A. Miller, Helena C. Chui, Irina Alafuzoff, Päivi Hartikainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl W. Cotman, M. Teresa Tũón, M. Cristina Caballero Martínez, David G. Munoz, Steven L. Carroll, Daniel Marson, Peter F. Riederer, Nenad Bogdanovic, Gerard D. Schellenberg, Hakon Hakonarson, John Q. Trojanowski, Virginia M.Y. Lee

Research output: Contribution to journalArticle

295 Scopus citations

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 × 10 11; odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 × 10 4). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Original languageEnglish (US)
Pages (from-to)234-239
Number of pages6
JournalNature genetics
Volume42
Issue number3
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Genetics

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    Van Deerlin, V. M., Sleiman, P. M. A., Martinez-Lage, M., Chen-Plotkin, A., Wang, L. S., Graff-Radford, N. R., Dickson, D. W., Rademakers, R., Boeve, B. F., Grossman, M., Arnold, S. E., Mann, D. M. A., Pickering-Brown, S. M., Seelaar, H., Heutink, P., Van Swieten, J. C., Murrell, J. R., Ghetti, B., Spina, S., ... Lee, V. M. Y. (2010). Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nature genetics, 42(3), 234-239. https://doi.org/10.1038/ng.536