Frontotemporal dementia and its subtypes: a genome-wide association study.
Frontotemporal dementia and its subtypes: a genome-wide association study.
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DOI：
10.1016/s1474-4422(14)70065-1
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发表时间：
2014-07
期刊：
影响因子：
48
通讯作者：
Momeni, Parastoo
中科院分区：
文献类型：
--
作者：
Ferrari, Raffaele;Hernandez, Dena G.;Nalls, Michael A.;Rohrer, Jonathan D.;Ramasamy, Adaikalavan;Kwok, John B. J.;Dobson-Stone, Carol;Brooks, William S.;Schofield, Peter R.;Halliday, Glenda M.;Hodges, John R.;Piguet, Olivier;Bartley, Lauren;Thompson, Elizabeth;Haan, Eric;Hernandez, Isabel;Ruiz, Agustin;Boada, Merce;Borroni, Barbara;Padovani, Alessandro;Cruchaga, Carlos;Cairns, Nigel J.;Benussi, Luisa;Binetti, Giuliano;Ghidoni, Roberta;Forloni, Gianluigi;Galimberti, Daniela;Fenoglio, Chiara;Serpente, Maria;Scarpini, Elio;Clarimon, Jordi;Lleo, Alberto;Blesa, Rafael;Waldo, Maria Landqvist;Nilsson, Karin;Nilsson, Christer;Mackenzie, Ian R. A.;Hsiung, Ging-Yuek R.;Mann, David M. A.;Grafman, Jordan;Morris, Christopher M.;Attems, Johannes;Griffiths, Timothy D.;McKeith, Ian G.;Thomas, Alan J.;Pietrini, P.;Huey, Edward D.;Wassermann, Eric M.;Baborie, Atik;Jaros, Evelyn;Tierney, Michael C.;Pastor, Pau;Razquin, Cristina;Ortega-Cubero, Sara;Alonso, Elena;Perneczky, Robert;Diehl-Schmid, Janine;Alexopoulos, Panagiotis;Kurz, Alexander;Rainero, Innocenzo;Rubino, Elisa;Pinessi, Lorenzo;Rogaeva, Ekaterina;St George-Hyslop, Peter;Rossi, Giacomina;Tagliavini, Fabrizio;Giaccone, Giorgio;Rowe, James B.;Schlachetzki, Johannes C. M.;Uphill, James;Collinge, John;Mead, Simon;Danek, Adrian;Van Deerlin, Vivianna M.;Grossman, Murray;Trojanowski, John Q.;van der Zee, Julie;Deschamps, William;Van Langenhove, Tim;Cruts, Marc;Van Broeckhoven, Christine;Cappa, Stefano F.;Le Ber, Isabelle;Hannequin, Didier;Golfier, Veronique;Vercelletto, Martine;Brice, Alexis;Nacmias, Benedetta;Sorbi, Sandra;Bagnoli, Silvia;Piaceri, Irene;Nielsen, Jorgen E.;Hjermind, Lena E.;Riemenschneider, Matthias;Mayhaus, Manuel;Ibach, Bernd;Gasparoni, Gilles;Pichler, Sabrina;Gu, Wei;Rossor, Martin N.;Fox, Nick C.;Warren, Jason D.;Spillantini, Maria Grazia;Morris, Huw R.;Rizzu, Patrizia;Heutink, Peter;Snowden, Julie S.;Rollinson, Sara;Richardson, Anna;Gerhard, Alexander;Bruni, Amalia C.;Maletta, Raffaele;Frangipane, Francesca;Cupidi, Chiara;Bernardi, Livia;Anfossi, Maria;Gallo, Maura;Conidi, Maria Elena;Smirne, Nicoletta;Rademakers, Rosa;Baker, Matt;Dickson, Dennis W.;Graff-Radford, Neill R.;Petersen, Ronald C.;Knopman, David;Josephs, Keith A.;Boeve, Bradley F.;Parisi, Joseph E.;Seeley, William W.;Miller, Bruce L.;Karydas, Anna M.;Rosen, Howard;van Swieten, John C.;Dopper, Elise G. P.;Seelaar, Harro;Al Pijnenburg, Yolande;Scheltens, Philip;Logroscino, Giancarlo;Capozzo, Rosa;Novelli, Valeria;Puca, Annibale A.;Franceschi, Massimo;Postiglione, Alfredo;Milan, Graziella;Sorrentino, Paolo;Kristiansen, Mark;Chiang, Huei-Hsin;Graff, Caroline;Pasquier, Florence;Rollin, Adeline;Deramecourt, Vincent;Lebert, Florence;Kapogiannis, Dimitrios;Ferrucci, Luigi;Pickering-Brown, Stuart;Singleton, Andrew B.;Hardy, John;Momeni, Parastoo
额颞叶痴呆 (FTD) 是一种复杂的疾病，其特征是广泛的临床表现、不同的病理特征和遗传变异。三个基因（MAPT、GRN 和 C9orf72）的突变与 FTD 相关。我们试图确定与该疾病相关的新遗传风险位点。我们对临床 FTD 进行了两阶段全基因组关联研究，分析了 3526 名 FTD 患者和 9402 名健康对照者的样本。所有参与者都有欧洲血统。在发现阶段（来自 2154 名 FTD 患者和 4308 名对照组的样本），我们对每种 FTD 亚型（行为变异 FTD、语义痴呆、进行性非流利性失语症以及 FTD 与运动神经元疾病重叠 [FTD-MND]）进行了单独的关联分析，然后对整个数据集进行荟萃分析。我们在独立样本系列（来自 1372 名患者和 5094 名对照的样本）中继续复制新的暗示性位点，然后对相关（p<5 × 10−8）和暗示性单核苷酸多态性进行联合相位和脑表达以及甲基化数量性状基因座分析。我们发现了超过全基因组显着性阈值 (p<5 × 10−8) 的新关联，其中包含整个队列中 6p21.3 处的 HLA 基因座。我们还在 11q14 确定了行为 FTD 亚型的一个潜在新基因座，包括 RAB38/CTSC。表达和甲基化数量性状基因座数据的分析表明这些基因座可能影响表达和甲基化。我们的研究结果表明，免疫系统过程（链接到 6p21.3）以及可能的溶酶体和自噬途径（链接到 11q14）可能参与 FTD。我们的研究结果需要被复制，以更好地定义新发现的基因座与疾病的关联，并可能阐明导致 FTD 的病理机制。国家神经疾病和中风研究所、国家老龄化研究所、Wellcome/MRC 帕金森病中心、英国阿尔茨海默病研究中心和德克萨斯理工大学健康科学中心。
Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms. We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis. Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD. The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.