Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.
Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.
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DOI：
10.1038/s41380-018-0112-7
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发表时间：
2020-08
影响因子：
11
通讯作者：
Farrer LA
中科院分区：
文献类型：
--
作者：
Bis JC;Jian X;Kunkle BW;Chen Y;Hamilton-Nelson KL;Bush WS;Salerno WJ;Lancour D;Ma Y;Renton AE;Marcora E;Farrell JJ;Zhao Y;Qu L;Ahmad S;Amin N;Amouyel P;Beecham GW;Below JE;Campion D;Cantwell L;Charbonnier C;Chung J;Crane PK;Cruchaga C;Cupples LA;Dartigues JF;Debette S;Deleuze JF;Fulton L;Gabriel SB;Genin E;Gibbs RA;Goate A;Grenier-Boley B;Gupta N;Haines JL;Havulinna AS;Helisalmi S;Hiltunen M;Howrigan DP;Ikram MA;Kaprio J;Konrad J;Kuzma A;Lander ES;Lathrop M;Lehtimäki T;Lin H;Mattila K;Mayeux R;Muzny DM;Nasser W;Neale B;Nho K;Nicolas G;Patel D;Pericak-Vance MA;Perola M;Psaty BM;Quenez O;Rajabli F;Redon R;Reitz C;Remes AM;Salomaa V;Sarnowski C;Schmidt H;Schmidt M;Schmidt R;Soininen H;Thornton TA;Tosto G;Tzourio C;van der Lee SJ;van Duijn CM;Valladares O;Vardarajan B;Wang LS;Wang W;Wijsman E;Wilson RK;Witten D;Worley KC;Zhang X;Alzheimer’s Disease Sequencing Project;Bellenguez C;Lambert JC;Kurki MI;Palotie A;Daly M;Boerwinkle E;Lunetta KL;Destefano AL;Dupuis J;Martin ER;Schellenberg GD;Seshadri S;Naj AC;Fornage M;Farrer LA
阿尔茨海默病测序项目（ADSP）对5，740例迟发性阿尔茨海默病（AD）病例和5，096例主要为欧洲血统（EA）的认知正常对照进行了全外显子组测序，其中218例病例和177例对照为加勒比西班牙裔（CH）。使用基于年龄、性别和APOE的风险评分和家族史来选择最有可能携带新型AD风险变体的病例和最不可能在85岁时发展为AD的对照。我们测试了约150万个单核苷酸变异（SNV）和50，000个插入-缺失多态性（indels）与AD的相关性，使用考虑单个变异的多个模型以及基于基因的测试聚合罕见，预测功能和功能丧失变异。在4个独立样本中评估了16个单一变异体和19个基因的复制情况，这些变异体和基因在多重检验校正后符合显著或暗示性关联的标准; 3个样本进行了全外显子组测序（2，778例，7，262例对照），1个样本进行了全基因组基因分型（9，343例，11，527例对照）。发现样本中的最高发现也在ADSP全基因组测序的基于家族的数据集中进行了随访（42个EA家族的197个成员和157个CH家族的501个成员）。我们在先前与AD相关的基因中鉴定了新的和预测的功能性遗传变异。我们还发现了三个新基因的关联：IGHG 3（p = 9.8 × 10−7），一个抗体与β-淀粉样蛋白相互作用的免疫球蛋白基因，一个长的非编码RNA AC099552.4（p = 1.2 × 10−7），和一个锌指蛋白ZNF 655（基于基因的p = 5.0 × 10−6）。后两者表明转录调控在AD发病机制中的重要作用。
The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
11.9
作者：
Hashimoto, Ryota;Noguchi, Hiroko;Kunugi, Hiroshi
通讯作者：
Kunugi, Hiroshi
影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
8.2
作者：
Friedrichs, Patrick;Schlotterer, Andrea;Hammes, Hans-Peter
通讯作者：
Hammes, Hans-Peter