David A. Flockhart

School of Medicine, Medicine, Clinical Pharmacology

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

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; et al. (Profiled Authors: Bernardino Ghetti; Jill R. Murrell)

Nature Genetics. 2010;42(3):234-239.

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 × 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 × 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. © 2010 Nature America, Inc. All rights reserved.

PMID: 20154673     PMCID: PMC2828525

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