Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions

VM Van Deerlin, PMA Sleiman, M Martinez-Lage, A Chen-Plotkin, LS (Li-San) Wang, NR Graff-Radford, DW Dickson, R Rademakers, BF Boeve, M Grossman, SE Arnold, DMA Mann, SM Pickering-Brown, Harro Seelaar, P Heutink, J.C. van Swieten, JR Murrell, B Ghetti, S Spina, J GrafmanJ Hodges, MG Spillantini, S Gilman, AP Lieberman, JA Kaye, RL Woltjer, EH Bigio, M Mesulam, S Al-Sarraj, C Troakes, RN Rosenberg, CL White, I Ferrer, A Llado, M (Manuela) Neumann, HA Kretzschmar, CM Hulette, KA Welsh-Bohmer, BL Miller, A Alzualde, AL de Munain, AC McKee, M Gearing, AI Levey, JJ Lah, J Hardy, JD Rohrer, T Lashley, IRA Mackenzie, HH Feldman, RL Hamilton, ST DeKosky, JA Zee, S Kumar-Singh, C van Broeckhoven, R Mayeux, JPG Vonsattel, JC Troncoso, JJ Kril, JBJ Kwok, GM Halliday, TD Bird, PG Ince, PJ Shaw, NJ Cairns, JC Morris, CA McLean, C DeCarli, WG Ellis, SH Freeman, MP Frosch, JH Growdon, DP Perl, M Sano, DA Bennett, JA Schneider, TG Beach, EM Reiman, BK Woodruff, J Cummings, HV Vinters, CA Miller, HC Chui, I Alafuzoff, P Hartikainen, D Seilhean, D Galasko, E Masliah, CW Cotman, MT Tunon, MCC Martinez, DG Munoz, SL Carroll, D Marson, PF Riederer, N Bogdanovic, GD Schellenberg, H Hakonarson, JQ Trojanowski, VMY Lee

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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) 1. 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.
Original languageUndefined/Unknown
Pages (from-to)234-U34
Number of pages8
JournalNature Genetics
Volume42
Issue number3
DOIs
Publication statusPublished - 2010

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