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

By V. V. Van Deerlin, P. Sleiman, M. Martinez-Lage, A. Chen-Plotkin, Li-San Wang, N. Graff-Radford, Dennis W. Dickson, Rosa Rademakers, Brad Boeve, Murray C. Grossman and 90 more. Nature Genetics, 2010

595 citations recorded by the source corpus.

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.

Subfields: Neurology

View Paper: https://www.semanticscholar.org/paper/e2335d6afdf88a2610672f6b8b49ae64464d9355

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In Neurology

Citations in the corpus

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD (2011, background): “A recent GWAS for FTD also identified this locus (Van Deerlin et al., 2010).”
The Post-GWAS Era: From Association to Function. (2018, background): “6).(96) In the years since, this locus has been conclusively linked to the target TMEM106B by multiple groups,(97,98) and TMEM106B has been shown to localize to and affect the function of lysosomes.”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, unknown): “…within C9ORF72 Genome-wide association studies (GWASs) of familial ALS patients in the Finish population, as well as in sporadic ALS, demonstrated the presence of a major ALS locus on chromosome 9p21 (Laaksovirta et al., 2010; Shatunov et al., 2010; Van Deerlin et al., 2010; van Es et al., 2009).”
Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis (2011, unknown): “…region has been identified in several large independent genomewide association studies (GWAS) of both ALS and FTD, implicating the genetic defect at chromosome 9p in sporadic forms of both diseases (Laaksovirta et al., 2010; Shatunov et al., 2010; Van Deerlin et al., 2010; van Es et al., 2009).”