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