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


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; Grafman, J; Hodges, J; Spillantini, M G; Gilman, S; Lieberman, A P; Kaye, J A; Woltjer, R L; Bigio, E H; Mesulam, M; Al-Sarraj, S; Troakes, C; Rosenberg, R N; White, C L; Ferrer, I; Lladó, A; Neumann, M; Kretzschmar, H A; Hulette, C M; Welsh-Bohmer, K A; Miller, B L; Alzualde, A; Lopez de Munain, A; McKee, A C; Gearing, M; Levey, A I; Lah, J J; Hardy, J; Rohrer, J D; Lashley, T; Mackenzie, I R A; Feldman, H H; Hamilton, R L; Dekosky, S T; van der Zee, J; Kumar-Singh, S; Van Broeckhoven, C; Mayeux, R; Vonsattel, J P G; Troncoso, J C; Kril, J J; Kwok, J B J; Halliday, G M; Bird, T D; Ince, P G; Shaw, P J; Cairns, N J; Morris, J C; McLean, C A; DeCarli, C; Ellis, W G; Freeman, S H; Frosch, M P; Growdon, J H; Perl, D P; Sano, M; Bennett, D A; Schneider, J A; Beach, T G; Reiman, E M; Woodruff, B K; Cummings, J; Vinters, H V; Miller, C A; Chui, H C; Alafuzoff, I; Hartikainen, P; Seilhean, D; Galasko, D; Masliah, E; Cotman, C W; Tuñón, M T; Martínez, M C C; Munoz, D G; Carroll, S L; Marson, D; Riederer, P F; Bogdanovic, N; Schellenberg, G D; Hakonarson, H; Trojanowski, J Q; 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.

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.

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Genetics
Language:English
Date:2010
Deposited On:03 Feb 2011 19:34
Last Modified:05 Dec 2023 02:46
Publisher:Nature Publishing Group
ISSN:1061-4036
Additional Information:Comment in: Nat Genet. 2010 Mar;42(3):189-90.
OA Status:Closed
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/ng.536
PubMed ID:20154673