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

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.

• Authors: Vivianna M Van Deerlin, Patrick M A Sleiman, Maria Martinez-Lage, Alice Chen-Plotkin, Li-San Wang, Neill R Graff-Radford, Dennis W Dickson, Rosa Rademakers, Bradley F Boeve, Murray Grossman, Steven E Arnold, David M A Mann, Stuart M Pickering-Brown, Harro Seelaar, Peter Heutink, John C van Swieten, Jill R Murrell, Bernardino Ghetti, Salvatore Spina, Jordan Grafman, John Hodges, Maria Grazia Spillantini, Sid Gilman, Andrew P Lieberman, Jeffrey A Kaye, Randall L Woltjer, Eileen H Bigio, Marsel Mesulam, Safa Al-Sarraj, Claire Troakes, Roger N Rosenberg, Charles L White 3rd, Isidro Ferrer, Albert Lladó, Manuela Neumann, Hans A Kretzschmar, Christine Marie Hulette, Kathleen A Welsh-Bohmer, Bruce L Miller, Ainhoa Alzualde, Adolfo Lopez de Munain, Ann C McKee, Marla Gearing, Allan I Levey, James J Lah, John Hardy, Jonathan D Rohrer, Tammaryn Lashley, Ian R A Mackenzie, Howard H Feldman, Ronald L Hamilton, Steven T Dekosky, Julie van der Zee, Samir Kumar-Singh, Christine Van Broeckhoven, Richard Mayeux, Jean Paul G Vonsattel, Juan C Troncoso, Jillian J Kril, John B J Kwok, Glenda M Halliday, Thomas D Bird, Paul G Ince, Pamela J Shaw, Nigel J Cairns, John C Morris, Catriona Ann McLean, Charles DeCarli, William G Ellis, Stefanie H Freeman, Matthew P Frosch, John H Growdon, Daniel P Perl, Mary Sano, David A Bennett, Julie A Schneider, Thomas G Beach, Eric M Reiman, Bryan K Woodruff, Jeffrey Cummings, Harry V Vinters, Carol A Miller, Helena C Chui, Irina Alafuzoff, Päivi Hartikainen, Danielle Seilhean, Douglas Galasko, Eliezer Masliah, Carl W Cotman, M Teresa Tuñón, M Cristina Caballero Martínez, 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
• Journal: Nature genetics (Nat Genet) Vol. 42 Issue 3 Pg. 234-9 (Mar 2010) ISSN: 1546-1718 [Electronic] United States
• PMID: 20154673 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• GRN protein, human
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Progranulins

Topics

• Case-Control Studies
• Chromosomes, Human, Pair 7
• DNA-Binding Proteins (metabolism)
• Frontotemporal Lobar Degeneration (genetics, metabolism)
• Gene Frequency
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotype
• Humans
• Inclusion Bodies (genetics, metabolism)
• Intercellular Signaling Peptides and Proteins (genetics)
• Linkage Disequilibrium
• Membrane Proteins (genetics)
• Polymorphism, Single Nucleotide
• Progranulins