Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
2010 (English)In: Nature Genetics, ISSN 1061-4036, Vol. 42, no 3, 234-239 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2010. Vol. 42, no 3, 234-239 p.
Cell and Molecular Biology Medical Genetics
IdentifiersURN: urn:nbn:se:uu:diva-120759DOI: 10.1038/ng.536ISI: 000274912400012PubMedID: 20154673OAI: oai:DiVA.org:uu-120759DiVA: diva2:303950