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

  • Author(s): Van Deerlin, Vivianna M
  • Sleiman, Patrick MA
  • 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 MA
  • 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
  • Lopez de Munain, Adolfo
  • McKee, Ann C
  • Gearing, Marla
  • Levey, Allan I
  • Lah, James J
  • Hardy, John
  • Rohrer, Jonathan D
  • Lashley, Tammaryn
  • Mackenzie, Ian RA
  • 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 BJ
  • 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
  • et al.

Published Web Location

https://doi.org/10.1038/ng.536
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 x 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 x 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.

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