Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
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阿尔茨海默病的常见变异和多基因风险评分的风险分层。

DOI:
10.1038/s41467-021-22491-8
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发表时间:
2021-06-07
影响因子:
16.6
通讯作者:
Ruiz A
Ruiz A
中科院分区:
综合性期刊1区
文献类型:
--
作者:
de Rojas I;Moreno-Grau S;Tesi N;Grenier-Boley B;Andrade V;Jansen IE;Pedersen NL;Stringa N;Zettergren A;Hernández I;Montrreal L;Antúnez C;Antonell A;Tankard RM;Bis JC;Sims R;Bellenguez C;Quintela I;González-Perez A;Calero M;Franco-Macías E;Macías J;Blesa R;Cervera-Carles L;Menéndez-González M;Frank-García A;Royo JL;Moreno F;Huerto Vilas R;Baquero M;Diez-Fairen M;Lage C;García-Madrona S;García-González P;Alarcón-Martín E;Valero S;Sotolongo-Grau O;Ullgren A;Naj AC;Lemstra AW;Benaque A;Pérez-Cordón A;Benussi A;Rábano A;Padovani A;Squassina A;de Mendonça A;Arias Pastor A;Kok AAL;Meggy A;Pastor AB;Espinosa A;Corma-Gómez A;Martín Montes A;Sanabria Á;DeStefano AL;Schneider A;Haapasalo A;Kinhult Ståhlbom A;Tybjærg-Hansen A;Hartmann AM;Spottke A;Corbatón-Anchuelo A;Rongve A;Borroni B;Arosio B;Nacmias B;Nordestgaard BG;Kunkle BW;Charbonnier C;Abdelnour C;Masullo C;Martínez Rodríguez C;Muñoz-Fernandez C;Dufouil C;Graff C;Ferreira CB;Chillotti C;Reynolds CA;Fenoglio C;Van Broeckhoven C;Clark C;Pisanu C;Satizabal CL;Holmes C;Buiza-Rueda D;Aarsland D;Rujescu D;Alcolea D;Galimberti D;Wallon D;Seripa D;Grünblatt E;Dardiotis E;Düzel E;Scarpini E;Conti E;Rubino E;Gelpi E;Rodriguez-Rodriguez E;Duron E;Boerwinkle E;Ferri E;Tagliavini F;Küçükali F;Pasquier F;Sanchez-Garcia F;Mangialasche F;Jessen F;Nicolas G;Selbæk G;Ortega G;Chêne G;Hadjigeorgiou G;Rossi G;Spalletta G;Giaccone G;Grande G;Binetti G;Papenberg G;Hampel H;Bailly H;Zetterberg H;Soininen H;Karlsson IK;Alvarez I;Appollonio I;Giegling I;Skoog I;Saltvedt I;Rainero I;Rosas Allende I;Hort J;Diehl-Schmid J;Van Dongen J;Vidal JS;Lehtisalo J;Wiltfang J;Thomassen JQ;Kornhuber J;Haines JL;Vogelgsang J;Pineda JA;Fortea J;Popp J;Deckert J;Buerger K;Morgan K;Fließbach K;Sleegers K;Molina-Porcel L;Kilander L;Weinhold L;Farrer LA;Wang LS;Kleineidam L;Farotti L;Parnetti L;Tremolizzo L;Hausner L;Benussi L;Froelich L;Ikram MA;Deniz-Naranjo MC;Tsolaki M;Rosende-Roca M;Löwenmark M;Hulsman M;Spallazzi M;Pericak-Vance MA;Esiri M;Bernal Sánchez-Arjona M;Dalmasso MC;Martínez-Larrad MT;Arcaro M;Nöthen MM;Fernández-Fuertes M;Dichgans M;Ingelsson M;Herrmann MJ;Scherer M;Vyhnalek M;Kosmidis MH;Yannakoulia M;Schmid M;Ewers M;Heneka MT;Wagner M;Scamosci M;Kivipelto M;Hiltunen M;Zulaica M;Alegret M;Fornage M;Roberto N;van Schoor NM;Seidu NM;Banaj N;Armstrong NJ;Scarmeas N;Scherbaum N;Goldhardt O;Hanon O;Peters O;Skrobot OA;Quenez O;Lerch O;Bossù P;Caffarra P;Dionigi Rossi P;Sakka P;Mecocci P;Hoffmann P;Holmans PA;Fischer P;Riederer P;Yang Q;Marshall R;Kalaria RN;Mayeux R;Vandenberghe R;Cecchetti R;Ghidoni R;Frikke-Schmidt R;Sorbi S;Hägg S;Engelborghs S;Helisalmi S;Botne Sando S;Kern S;Archetti S;Boschi S;Fostinelli S;Gil S;Mendoza S;Mead S;Ciccone S;Djurovic S;Heilmann-Heimbach S;Riedel-Heller S;Kuulasmaa T;Del Ser T;Lebouvier T;Polak T;Ngandu T;Grimmer T;Bessi V;Escott-Price V;Giedraitis V;Deramecourt V;Maier W;Jian X;Pijnenburg YAL;EADB contributors;GR@ACE study group;DEGESCO consortium;IGAP (ADGC, CHARGE, EADI, GERAD);PGC-ALZ consortia;Kehoe PG;Garcia-Ribas G;Sánchez-Juan P;Pastor P;Pérez-Tur J;Piñol-Ripoll G;Lopez de Munain A;García-Alberca JM;Bullido MJ;Álvarez V;Lleó A;Real LM;Mir P;Medina M;Scheltens P;Holstege H;Marquié M;Sáez ME;Carracedo Á;Amouyel P;Schellenberg GD;Williams J;Seshadri S;van Duijn CM;Mather KA;Sánchez-Valle R;Serrano-Ríos M;Orellana A;Tárraga L;Blennow K;Huisman M;Andreassen OA;Posthuma D;Clarimón J;Boada M;van der Flier WM;Ramirez A;Lambert JC;van der Lee SJ;Ruiz A

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阿尔茨海默病的遗传发现是我们理解的驱动因素,多遗传风险分层可以有助于规划可行和有效的预防和治疗临床试验。我们首先进行了一项大型遗传关联研究,合并了所有可用的病例对照数据集和代理研究结果(发现n = 409,435,验证规模n = 58,190)。在这里,我们添加了6个与阿尔茨海默病风险相关的变异(APP, CHRNE, PRKD3/NDUFAF7, PLCG2和SHARPIN基因中的两个外显子变异)。多基因风险评分评估和APOE分层显示APOE携带者阿尔茨海默病患者发病的中位年龄有4至5.5岁的差异。由于这项研究,APP的潜在机制可以被研究来完善淀粉样蛋白级联,多基因风险评分提供了一个选择阿尔茨海默病高风险个体的工具。已知的基因位点只占阿尔茨海默病遗传贡献的一小部分。在这里,作者进行了一项包含409,435个个体的大型全基因组荟萃分析,发现了6个新的基因位点,并证明了阿尔茨海默病多基因风险评分的有效性。
Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.
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