[1] Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. [2] These authors contributed equally to this work.
Nat Genet. 2010 Mar;42(3):234-9. doi: 10.1038/ng.536. Epub 2010 Feb 14.
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.
额颞叶变性（FTLD）是早发性痴呆的第二大常见原因。主要的神经病理学是 FTLD 与 TAR DNA 结合蛋白（TDP-43）包涵体（FTLD-TDP）。FTLD-TDP 常为家族性的，是由 GRN（编码颗粒蛋白前体）突变引起的。我们通过对 515 名 FTLD-TDP 患者进行全基因组关联研究，组建了一个国际合作组织，以确定 FTLD-TDP 的易感基因座。我们发现 FTLD-TDP 与多个 SNP 相关联，这些 SNP 映射到包含 TMEM106B 的单个连锁不平衡块上。在 Bonferroni 校正后，有三个 SNP 保留了全基因组意义（最高 SNP rs1990622，P = 1.08 x 10(-11)；优势比，小等位基因（C）0.61，95%CI 0.53-0.71）。在 89 例 FTLD-TDP 病例中进行了关联复制（rs1990622；P = 2 x 10(-4)）。TMEM106B 变体可能通过增加 TMEM106B 的表达来增加 FTLD-TDP 的风险。TMEM106B 变体也会增加携带 GRN 突变的个体患 FTLD-TDP 的遗传风险。我们的数据表明 TMEM106B 中的变体是 FTLD-TDP 的一个强危险因素，提示存在潜在的致病机制。
