Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.
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DOI：
10.1038/ng.536
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发表时间：
2010-03
期刊：
影响因子：
30.8
通讯作者：
Lee, Virginia M-Y
中科院分区：
文献类型：
--
作者：
Van Deerlin, Vivianna M.;Sleiman, Patrick M. A.;Martinez-Lage, Maria;Chen-Plotkin, Alice;Wang, Li-San;Graff-Radford, Neill R.;Dickson, Dennis W.;Rademakers, Rosa;Boeve, Bradley F.;Grossman, Murray;Arnold, Steven E.;Mann, David M. A.;Pickering-Brown, Stuart M.;Seelaar, Harro;Heutink, Peter;van Swieten, John C.;Murrell, Jill R.;Ghetti, Bernardino;Spina, Salvatore;Grafman, Jordan;Hodges, John;Spillantini, Maria Grazia;Gilman, Sid;Lieberman, Andrew P.;Kaye, Jeffrey A.;Woltjer, Randall L.;Bigio, Eileen H.;Mesulam, Marsel;al-Sarraj, Safa;Troakes, Claire;Rosenberg, Roger N.;White, Charles L., III;Ferrer, Isidro;Llado, Albert;Neumann, Manuela;Kretzschmar, Hans A.;Hulette, Christine Marie;Welsh-Bohmer, Kathleen A.;Miller, Bruce L.;Alzualde, Ainhoa;Lopez de Munain, Adolfo;McKee, Ann C.;Gearing, Marla;Levey, Allan I.;Lah, James J.;Hardy, John;Rohrer, Jonathan D.;Lashley, Tammaryn;Mackenzie, Ian R. A.;Feldman, Howard H.;Hamilton, Ronald L.;Dekosky, Steven T.;van der Zee, Julie;Kumar-Singh, Samir;Van Broeckhoven, Christine;Mayeux, Richard;Vonsattel, Jean Paul G.;Troncoso, Juan C.;Kril, Jillian J.;Kwok, John B. J.;Halliday, Glenda M.;Bird, Thomas D.;Ince, Paul G.;Shaw, Pamela J.;Cairns, Nigel J.;Morris, John C.;McLean, Catriona Ann;DeCarli, Charles;Ellis, William G.;Freeman, Stefanie H.;Frosch, Matthew P.;Growdon, John H.;Perl, Daniel P.;Sano, Mary;Bennett, David A.;Schneider, Julie A.;Beach, Thomas G.;Reiman, Eric M.;Woodruff, Bryan K.;Cummings, Jeffrey;Vinters, Harry V.;Miller, Carol A.;Chui, Helena C.;Alafuzoff, Irina;Hartikainen, Paivi;Seilhean, Danielle;Galasko, Douglas;Masliah, Eliezer;Cotman, Carl W.;Tunon, M. Teresa;Martinez, M. Cristina Caballero;Munoz, David G.;Carroll, Steven L.;Marson, Daniel;Riederer, Peter F.;Bogdanovic, Nenad;Schellenberg, Gerard D.;Hakonarson, Hakon;Trojanowski, John Q.;Lee, Virginia M-Y
额颞叶变性（FTLD）是老年性痴呆的第二大常见原因。主要的神经病理学是FTLD伴TAR DNA结合蛋白（TDP-43）包涵体（FTLD-TDP）。FTLD-TDP通常是由颗粒蛋白前体（GRN）突变引起的家族性疾病。我们组织了一个国际合作，使用全基因组关联（GWA）来确定FTLD-TDP的易感基因座。我们在对515例FTLD-TDP病例进行的GWA研究（GWAS）中发现，FTLD-TDP与映射到7 p21上包含TMEM 106 B的单个连锁不平衡（LD）区块的多个SNP相关。在Bonferroni校正后，三个SNP保留了全基因组显著性;最高SNP rs 1990622（P=1.08×10−11;比值比（OR）次要等位基因（C）0.61，95% CI 0.53-0.71）。该关联在89例FTLD-TDP病例中重复（rs 1990622; P=2×10−4）。TMEM 106 B变体可能通过增加TMEM 106 B表达而带来风险。TMEM 106 B变异也有助于GRN突变患者的FTLD-TDP遗传风险。我们的数据表明TMEM 106 B是FTLD-TDP的一个强风险因素，提示潜在的致病机制。
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 progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) 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 by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
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影响因子：
64.8
作者：
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通讯作者：
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