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

TitleCommon variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
Publication TypeJournal Article
Year of Publication2010
AuthorsVan 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
JournalNat Genet
Volume42
Issue3
Pagination234-9
Date Published2010 Mar
ISSN1546-1718
KeywordsCase-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.

DOI10.1038/ng.536
Alternate JournalNat. Genet.
PubMed ID20154673
PubMed Central IDPMC2828525
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