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

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)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an internation...

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Detalles Bibliográficos
Autores principales: Van Deerlin, Vivianna M., Sleiman, Patrick M. A., Martinez-Lage, Maria, Chen-Plotkin, Alice, Wang, Li-San, Graff-Radford, Neill R, Dickson, Dennis W., Rademakers, Rosa, Boeve, Bradley F., Grossman, Murray, Arnold, Steven E., Mann, David M.A., Pickering-Brown, Stuart M., Seelaar, Harro, Heutink, Peter, van Swieten, John C., Murrell, Jill R., Ghetti, Bernardino, Spina, Salvatore, Grafman, Jordan, Hodges, John, Spillantini, Maria Grazia, Gilman, Sid', Lieberman, Andrew P., Kaye, Jeffrey A., Woltjer, Randall L., Bigio, Eileen H, Mesulam, Marsel, al-Sarraj, Safa, Troakes, Claire, Rosenberg, Roger N., White, Charles L., Ferrer, Isidro, Lladó, Albert, Neumann, Manuela, Kretzschmar, Hans A., Hulette, Christine Marie, Welsh-Bohmer, Kathleen A., Miller, Bruce L, Alzualde, Ainhoa, de Munain, Adolfo Lopez, McKee, Ann C., Gearing, Marla, Levey, Allan I., Lah, James J., Hardy, John, Rohrer, Jonathan D., Lashley, Tammaryn, Mackenzie, Ian R.A., Feldman, Howard H., Hamilton, Ronald L., Dekosky, Steven T., van der Zee, Julie, Kumar-Singh, Samir, Van Broeckhoven, Christine, Mayeux, Richard, Vonsattel, Jean Paul G., Troncoso, Juan C., Kril, Jillian J, Kwok, John B.J., Halliday, Glenda M., Bird, Thomas D., Ince, Paul G., Shaw, Pamela J., Cairns, Nigel J., Morris, John C., McLean, Catriona Ann, DeCarli, Charles, Ellis, William G., Freeman, Stefanie H., Frosch, Matthew P., Growdon, John H., Perl, Daniel P., Sano, Mary, Bennett, David A., Schneider, Julie A., Beach, Thomas G., Reiman, Eric M., Woodruff, Bryan K., Cummings, Jeffrey, Vinters, Harry V., Miller, Carol A., Chui, Helena C., Alafuzoff, Irina, Hartikainen, Päivi, Seilhean, Danielle, Galasko, Douglas, Masliah, Eliezer, Cotman, Carl W., Tuñón, M. Teresa, Martínez, M. Cristina Caballero, Munoz, David G., Carroll, Steven L., Marson, Daniel, Riederer, Peter F., Bogdanovic, Nenad, Schellenberg, Gerard D., Hakonarson, Hakon, Trojanowski, John Q., Lee, Virginia M.-Y.
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828525/
https://www.ncbi.nlm.nih.gov/pubmed/20154673
http://dx.doi.org/10.1038/ng.536
Descripción
Sumario: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)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10(−11); odds ratio (OR) 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 by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.

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