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

Vivianna Van Deerlin, Patrick Sleiman, Maria Marinez-Lage, Alice Chen-Plotkin, Li-San Wang, Neill Graff-Radford, Dennis Dickson, Rosa Rademakers, Bradley Boeve, Murray Grossman, Steve Arnold, David Mann, Stuart Pickering-Brown, Harro Seelaar, Peter Heutink, John C van Swieten, Jill Murrell, Bernardino Ghetti, Salvatore Spina, Jordan GrafmanJohn Hodges, Maria Spillantini, Sid Gilman, Andrew Lieberman, Jeffrey Kaye, Randall Woltjer, Eileen Bigio, Marsel Mesulam, Safa al-Sarraj, Claire Troakes, Roger Rosenberg, Charles L White III, Isidro Ferrer, Albert Llado, Manuela Neumann, Hans Kretzschmar, Christine Hulette, Kathleen Welsh-Bohmer, Bruce Miller, Ainhoa Alzualde, Adolfo de Munain, Ann McKee, Marla Gearing, Allan Levey, James Lah, John Hardy, Jonathan Rohrer, Tammaryn Lashley, Ian Mackenzie, Howard Feldman, Ronald Hamilton, Steven Dekosky, Julie van der Zee, Samir Kumar-Singh, Christine Van Broeckhoven, Richard Mayeux, Jean Vonsattel, Juan Troncoso, Jillian Kril, John Kwok, Glenda Halliday, Thomas Bird, Paul Ince, Pamela Shaw, Nigel Cairns, John Morris, Catriona Ann McLean, Charles DeCarli, William Ellis, Stephanie Freeman, Matthew Frosch, John Growdon, Daniel Perl, Mary Sano, David Bennett, Julie Schneider, Thomas Beach, Eric Reiman, Brian Woodruff, Jeffrey Cummings, Harry Vinters, Carol Miller, Helena Chui, Irina Alafuzoff, Paivi Harkinkainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl Cotman, Maria Tunon, M Caballero Martinez, David G Munoz, Steven L Carroll, Daniel Marson, Peter F Riederer, Nenad Bogdanovic, Gerard D Schellenberg, Hakon Hakonarson, John Q Trojanowski, Virginia M-Y Lee

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326 Citations (Scopus)

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 i?? 10-11; odds ratio, minor allele (C) 0.61, 95 CI 0.53i??0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 i?? 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 languageEnglish
Pages (from-to)234 - 239
Number of pages6
JournalNature Genetics
Volume42
Issue number3
DOIs
Publication statusPublished - 2010

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