Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions by Van Deerlin Vivianna M, Sleiman Patrick M A, Martinez-Lage Maria, Chen-Plotkin Alice, Wang Li-San, Graff-Radford Neill R, Dickson Dennis W, Rademakers Rosa, Boeve Bradley F, Grossman Murray, Arnold Steven E, Mann David M A, Pickering-Brown Stuart M, Seelaar Harro, Heutink Peter, van Swieten John C, Murrell Jill R, Ghetti Bernardino, Spina Salvatore, Grafman Jordan, Hodges John, Spillantini Maria Grazia, Gilman Sid, Lieberman Andrew P, Kaye Jeffrey A, Woltjer Randall L, Bigio Eileen H, Mesulam Marsel, Al-Sarraj Safa, Troakes Claire, Rosenberg Roger N, White Charles L, Ferrer Isidro, Lladó Albert, Neumann Manuela, Kretzschmar Hans A, Hulette Christine Marie, Welsh-Bohmer Kathleen A, Miller Bruce L, Alzualde Ainhoa, Lopez de Munain Adolfo, McKee Ann C, Gearing Marla, Levey Allan I, Lah James J, Hardy John, Rohrer Jonathan D, Lashley Tammaryn, Mackenzie Ian R A, Feldman Howard H, Hamilton Ronald L, Dekosky Steven T, van der Zee Julie, Kumar-Singh Samir, Van Broeckhoven Christine, Mayeux Richard, Vonsattel Jean Paul G, Troncoso Juan C, Kril Jillian J, Kwok John B J, Halliday Glenda M, Bird Thomas D, Ince Paul G, Shaw Pamela J, Cairns Nigel J, Morris John C, McLean Catriona Ann, DeCarli Charles, Ellis William G, Freeman Stefanie H, Frosch Matthew P, Growdon John H, Perl Daniel P, Sano Mary, Bennett David A, Schneider Julie A, Beach Thomas G, Reiman Eric M, Woodruff Bryan K, Cummings Jeffrey, Vinters Harry V, Miller Carol A, Chui Helena C, Alafuzoff Irina, Hartikainen Päivi, Seilhean Danielle, Galasko Douglas, Masliah Eliezer, Cotman Carl W, Tuñón M Teresa, Martínez M Cristina Caballero, Munoz David G, Carroll Steven L, Marson Daniel, Riederer Peter F, Bogdanovic Nenad, Schellenberg Gerard D, Hakonarson Hakon, Trojanowski John Q, Lee Virginia M-Y in Nature genetics (2010). PubMed

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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