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Title | Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Van Deerlin VM, Sleiman PMA, Martinez-Lage M, Chen-Plotkin A, San Wang L-, 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 MGrazia, 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 CMarie, Welsh-Bohmer KA, Miller BL, Alzualde A, de Munain ALopez, 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 JPaul G, Troncoso JC, Kril JJ, Kwok JBJ, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CAnn, 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, M Tuñón T, M Martínez CCaballero, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM-Y |
Journal | Nat Genet |
Volume | 42 |
Issue | 3 |
Pagination | 234-9 |
Date Published | 2010 Mar |
ISSN | 1546-1718 |
Keywords | Case-Control Studies, Chromosomes, Human, Pair 7, DNA-Binding Proteins, Frontotemporal Lobar Degeneration, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Inclusion Bodies, Intercellular Signaling Peptides and Proteins, Linkage Disequilibrium, Membrane Proteins, Polymorphism, Single Nucleotide, Progranulins |
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. |
DOI | 10.1038/ng.536 |
Alternate Journal | Nat. Genet. |
PubMed ID | 20154673 |
PubMed Central ID | PMC2828525 |
Grant List | P30 AG013854 / AG / NIA NIH HHS / United States R01 NS044266 / NS / NINDS NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States 089701 / / Wellcome Trust / United Kingdom P30 AG028377 / AG / NIA NIH HHS / United States P50 AG008671 / AG / NIA NIH HHS / United States AG05146 / AG / NIA NIH HHS / United States R01 AG015116 / AG / NIA NIH HHS / United States P50 AG005142 / AG / NIA NIH HHS / United States AG16573 / AG / NIA NIH HHS / United States AG05138 / AG / NIA NIH HHS / United States AG10124 / AG / NIA NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States AG005681 / AG / NIA NIH HHS / United States NS44266 / NS / NINDS NIH HHS / United States P50 AG016574 / AG / NIA NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States P30 AG010129-19 / AG / NIA NIH HHS / United States AG19610 / AG / NIA NIH HHS / United States NS15655 / NS / NINDS NIH HHS / United States AG15116 / AG / NIA NIH HHS / United States AG12300 / AG / NIA NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States 019724 / / PHS HHS / United States AG08671 / AG / NIA NIH HHS / United States AG03991 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States AG005131 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States AG16570 / AG / NIA NIH HHS / United States UL1 RR025741 / RR / NCRR NIH HHS / United States P50 NS053488 / NS / NINDS NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P30 AG012300 / AG / NIA NIH HHS / United States NS038372 / NS / NINDS NIH HHS / United States AG13846 / AG / NIA NIH HHS / United States P50 AG016573 / AG / NIA NIH HHS / United States AG005136 / AG / NIA NIH HHS / United States AG02219 / AG / NIA NIH HHS / United States / / Intramural NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States P50 AG016570 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States P50 AG005136-27 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States P01 NS015655 / NS / NINDS NIH HHS / United States R01 AG018440 / AG / NIA NIH HHS / United States AG05133 / AG / NIA NIH HHS / United States G0701441 / / Medical Research Council / United Kingdom AG008017 / AG / NIA NIH HHS / United States G0301152 / / Medical Research Council / United Kingdom AG025688 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States AG17586 / AG / NIA NIH HHS / United States NS53488 / NS / NINDS NIH HHS / United States R37 AG018440 / AG / NIA NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States 75480 / / Canadian Institutes of Health Research / Canada AG010133 / AG / NIA NIH HHS / United States P01 AG002219 / AG / NIA NIH HHS / United States P50 NS038372 / NS / NINDS NIH HHS / United States AG033101 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States AG18440 / AG / NIA NIH HHS / United States AG16582 / AG / NIA NIH HHS / United States R01 NS065782 / NS / NINDS NIH HHS / United States AG10161 / AG / NIA NIH HHS / United States AG13854 / AG / NIA NIH HHS / United States P01 NS044233 / NS / NINDS NIH HHS / United States AG08702 / AG / NIA NIH HHS / United States P01 AG003949 / AG / NIA NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States P50 AG016582 / AG / NIA NIH HHS / United States AG16574 / AG / NIA NIH HHS / United States AG010129 / AG / NIA NIH HHS / United States P30 AG010124-14 / AG / NIA NIH HHS / United States AG05134 / AG / NIA NIH HHS / United States NS044233 / NS / NINDS NIH HHS / United States AG05142 / AG / NIA NIH HHS / United States AG028377 / AG / NIA NIH HHS / United States G0600676 / / Medical Research Council / United Kingdom AG03949 / AG / NIA NIH HHS / United States AG5131 / AG / NIA NIH HHS / United States P01 AG017586-109001 / AG / NIA NIH HHS / United States G9724461 / / Medical Research Council / United Kingdom G0601943 / / Medical Research Council / United Kingdom |