APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.
APOE-ε4 and BIN1 increase risk of Alzheimer's disease pathology but not specifically of Lewy body pathology.
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DOI：
10.1186/s40478-023-01626-6
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发表时间：
2023-09-12
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
路易体（LB）病理学通常发生在患有阿尔茨海默病（AD）病理学的个体中。然而，尚不清楚哪些遗传风险因素是AD病理学、LB病理学或AD-LB共同病理学的基础。值得注意的是，APOE-ε4是否独立于AD病理学影响LB病理学的风险是有争议的。我们采用文献中的标准，将来自国家阿尔茨海默病协调中心（NACC）和拉什大学医学中心的4，985名受试者分类为AD-LB共同病理（AD+LB+）、单一AD病理（AD+LB-）、单一LB病理（AD-LB+）或无病理（AD-LB-）。我们对每种疾病表型的每个亚群（NACC/Rush）进行了全基因组关联研究（GWAS）的荟萃分析，并与对照组（AD + LB-）进行了比较，并比较了AD+LB+组与AD+LB-组。与AD-LB-相比，APOE-ε4与AD+LB-和AD+LB+的风险显著相关。然而，与AD-LB-相比，APOE-ε4与AD-LB+风险无关，或与AD+LB-相比，与AD+LB+风险无关。在BIN 1位点的协会表现出定性相似的结果。这些结果表明，APOE-ε4是AD病理学的危险因素，但当与AD病理学分离时，不是LB病理学的危险因素。BIN 1风险变体也是如此。在迄今为止最大的AD-LB神经病理学GWAS中，这些发现区分了单一和双重AD-LB病理表型的遗传风险因素。与基于临床诊断的GWAS相比，我们的GWAS荟萃分析汇总统计量来自基于尸检病理学评估的表型，可能提供更准确的疾病特异性多基因风险评分，这可能受到未检测到的双重病理和痴呆类型临床误诊的混淆。在线版本包含补充材料，可通过10.1186/s40478-023-01626-6获得。
Lewy body (LB) pathology commonly occurs in individuals with Alzheimer’s disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether APOE-ε4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer’s Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD+LB+), sole AD pathology (AD+LB–), sole LB pathology (AD–LB+), or no pathology (AD–LB–). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD–LB–), and compared the AD+LB+ to AD+LB– groups. APOE-ε4 was significantly associated with risk of AD+LB– and AD+LB+ compared to AD–LB–. However, APOE-ε4 was not associated with risk of AD–LB+ compared to AD–LB– or risk of AD+LB+ compared to AD+LB–. Associations at the BIN1 locus exhibited qualitatively similar results. These results suggest that APOE-ε4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for BIN1 risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type. The online version contains supplementary material available at 10.1186/s40478-023-01626-6.
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影响因子：
30.8
作者：
Bellenguez, Celine;Kucukali, Fahri;Jansen, Iris E.;Kleineidam, Luca;Moreno-Grau, Sonia;Amin, Najaf;Naj, Adam C.;Campos-Martin, Rafael;Grenier-Boley, Benjamin;Andrade, Victor;Holmans, Peter A.;Boland, Anne;Damotte, Vincent;van der Lee, Sven J.;Costa, Marcos R.;Kuulasmaa, Teemu;Yang, Qiong;De Rojas, Itziar;Bis, Joshua C.;Yaqub, Amber;Prokic, Ivana;Chapuis, Julien;Ahmad, Shahzad;Giedraitis, Vilmantas;Aarsland, Dag;Garcia-Gonzalez, Pablo;Abdelnour, Carla;Alarcon-Martin, Emilio;Alcolea, Daniel;Alegret, Montserrat;Alvarez, Ignacio;Alvarez, Victoria;Armstrong, Nicola J.;Tsolaki, Anthoula;Antunez, Carmen;Appollonio, Ildebrando;Arcaro, Marina;Archetti, Silvana;Arias Pastor, Alfonso;Arosio, Beatrice;Athanasiu, Lavinia;Bailly, Henri;Banaj, Nerisa;Baquero, Miquel;Barral, Sandra;Beiser, Alexa;Pastor, Ana Belen;Below, Jennifer E.;Benchek, Penelope;Benussi, Luisa;Berr, Claudine;Besse, Celine;Bessi, Valentina;Binetti, Giuliano;Bizarro, Alessandra;Blesa, Rafael;Boada, Merce;Boerwinkle, Eric;Borroni, Barbara;Boschi, Silvia;Bossu, Paola;Brathen, Geir;Bressler, Jan;Bresner, Catherine;Brodaty, Henry;Brookes, Keeley J.;Ignacio Brusco, Luis;Buiza-Rueda, Dolores;Burger, Katharina;Burholt, Vanessa;Bush, William S.;Calero, Miguel;Cantwell, Laura B.;Chene, Genevieve;Chung, Jaeyoon;Cuccaro, Michael L.;Cecchetti, Roberta;Cervera-Carles, Laura;Charbonnier, Camille;Chen, Hung-Hsin;Chillotti, Caterina;Ciccone, Simona;Claassen, Jurgen A. H. R.;Clark, Christopher;Conti, Elisa;Corma-Gomez, Anais;Costantini, Emanuele;Custodero, Carlo;Daian, Delphine;Dalmasso, Maria Carolina;Daniele, Antonio;Dardiotis, Efthimios;Dartigues, Jean-Francois;de Deyn, Peter Paul;Lopes, Katia de Paiva;De Witte, Lot D.;Debette, Stephanie;Deckert, Jurgen;del Ser, Teodoro;Denning, Nicola;Destefano, Anita;Dichgans, Martin;Diehl-Schmid, Janine;Diez-Fairen, Monica;Rossi, Paolo Dionigi;Djurovic, Srdjan;Duron, Emmanuelle;Duzel, Emrah;Dufouil, Carole;Eiriksdottir, Gudny;Engelborghs, Sebastiaan;Escott-Price, Valentina;Espinosa, Ana;Ewers, Michael;Faber, Kelley M.;Fabrizio, Tagliavini;Nielsen, Sune Fallgaard;Fardo, David W.;Farotti, Lucia;Fenoglio, Chiara;Fernandez-Fuertes, Marta;Ferrari, Raffaele;Ferreira, Catarina B.;Ferri, Evelyn;Fin, Bertrand;Fischer, Peter;Fladby, Tormod;Fliessbach, Klaus;Fongang, Bernard;Fornage, Myriam;Fortea, Juan;Foroud, Tatiana M.;Fostinelli, Silvia;Fox, Nick C.;Franco-Macias, Emlio;Bullido, Maria J.;Frank-Garcia, Ana;Froelich, Lutz;Fulton-Howard, Brian;Galimberti, Daniela;Maria Garcia-Alberca, Jose;Garcia-Madrona, Sebastian;Garcia-Ribas, Guillermo;Ghidoni, Roberta;Giegling, Ina;Giorgio, Giaccone;Goate, Alison M.;Goldhardt, Oliver;Gomez-Fonseca, Duber;Gonzalez-Perez, Antonio;Graff, Caroline;Grande, Giulia;Green, Emma;Grimmer, Timo;Grunblatt, Edna;Grunin, Michelle;Gudnason, Vilmundur;Guetta-Baranes, Tamar;Haapasalo, Annakaisa;Hadjigeorgiou, Georgios;Haines, Jonathan L.;Hamilton-Nelson, Kara L.;Hampel, Harald;Hanon, Olivier;Hardy, John;Hartmann, Annette M.;Hausner, Lucrezia;Harwood, Janet;Heilmann-Heimbach, Stefanie;Helisalmi, Seppo;Heneka, Michael T.;Hernandez, Isabel;Herrmann, Martin J.;Hoffmann, Per;Holmes, Clive;Holstege, Henne;Huerto Vilas, Raquel;Hulsman, Marc;Humphrey, Jack;Biessels, Geert Jan;Jian, Xueqiu;Johansson, Charlotte;Jun, Gyungah R.;Kastumata, Yuriko;Kauwe, John;Kehoe, Patrick G.;Kilander, Lena;Stahlbom, Anne Kinhult;Kivipelto, Miia;Koivisto, Anne;Kornhuber, Johannes;Kosmidis, Mary H.;Kukull, Walter A.;Kuksa, Pavel P.;Kunkle, Brian W.;Kuzma, Amanda B.;Lage, Carmen;Laukka, Erika J.;Launer, Lenore;Lauria, Alessandra;Lee, Chien-Yueh;Lehtisalo, Jenni;Lerch, Ondrej;Lleo, Alberto;Longstreth, William, Jr.;Lopez, Oscar;Lopez de Munain, Adolfo;Love, Seth;Lowemark, Malin;Luckcuck, Lauren;Lunetta, Kathryn L.;Ma, Yiyi;Macias, Juan;Macleod, Catherine A.;Maier, Wolfgang;Mangialasche, Francesca;Spallazzi, Marco;Marquie, Marta;Marshall, Rachel;Martin, Eden R.;Martin Montes, Angel;Martinez Rodriguez, Carmen;Masullo, Carlo;Mayeux, Richard;Mead, Simon;Mecocci, Patrizia;Medina, Miguel;Meggy, Alun;Mehrabian, Shima;Mendoza, Silvia;Menendez-Gonzalez, Manuel;Mir, Pablo;Moebus, Susanne;Mol, Merel;Molina-Porcel, Laura;Montrreal, Laura;Morelli, Laura;Moreno, Fermin;Morgan, Kevin;Mosley, Thomas;Nothen, Markus M.;Muchnik, Carolina;Mukherjee, Shubhabrata;Nacmias, Benedetta;Ngandu, Tiia;Nicolas, Gael;Nordestgaard, Borge G.;Olaso, Robert;Orellana, Adelina;Orsini, Michela;Ortega, Gemma;Padovani, Alessandro;Paolo, Caffarra;Papenberg, Goran;Parnetti, Lucilla;Pasquier, Florence;Pastor, Pau;Peloso, Gina;Perez-Cordon, Alba;Perez-Tur, Jordi;Pericard, Pierre;Peters, Oliver;Pijnenburg, Yolande A. L.;Pineda, Juan A.;Pinol-Ripoll, Gerard;Pisanu, Laudia;Polak, Thomas;Popp, Julius;Posthuma, Danielle;Priller, Josef;Puerta, Raquel;Quenez, Olivier;Quintela, Ines;Thomassen, Jesper Qvist;Rabano, Alberto;Rainero, Innocenzo;Rajabli, Farid;Ramakers, Inez;Real, Luis M.;Reinders, Marcel J. T.;Reitz, Christiane;Reyes-Dumeyer, Dolly;Ridge, Perry;Riedel-Heller, Steffi;Riederer, Peter;Roberto, Natalia;Rodriguez-Rodriguez, Eloy;Rongve, Arvid;Rosas Allende, Irene;Rosende-Roca, Maitee;Luis Royo, Jose;Rubino, Elisa;Rujescu, Dan;Eugenia Saez, Maria;Sakka, Paraskevi;Saltvedt, Ingvild;Bernal Sanchez-Arjona, Maria;Sanchez-Garcia, Florentino;Sanchez Juan, Pascual;Sanchez-Valle, Raquel;Sando, Sigrid B.;Sarnowski, Chloe;Satizabal, Claudia L.;Scamosci, Michela;Scarmeas, Nikolaos;Scarpini, Elio;Scheltens, Philip;Scherbaum, Norbert;Scherer, Martin;Schmid, Matthias;Schneider, Anja;Schott, Jonathan M.;Selbaek, Geir;Seripa, Davide;Serrano, Manuel;Sha, Jin;Shadrin, Alexey A.;Skrobot, Olivia;Slifer, Susan;Snijders, Gijsje J. L.;Soininen, Hilkka;Solfrizzi, Vincenzo;Solomon, Alina;Song, Yeunjoo;Sorbi, Sandro;Sotolongo-Grau, Oscar;Spalletta, Gianfranco;Spottke, Annika;Squassina, Alessio;Stordal, Eystein;Pablo Tartan, Juan;Tarraga, Lluis;Tesi, Niccolo;Thalamuthu, Anbupalam;Thomas, Tegos;Tosto, Giuseppe;Traykov, Latchezar;Tremolizzo, Lucio;Tybjaerg-Hansen, Anne;Uitterlinden, Andre;Ullgren, Abbe;Ulstein, Ingun;Valero, Sergi;Valladares, Otto;Van Broeckhoven, Christine;Vance, Jeffery;Vardarajan, Badri N.;van der Lugt, Aad;Van Dongen, Jasper;van Rooij, Jeroen;van Swieten, John;Vandenberghe, Rik;Verhey, Frans;Vidal, Jean-Sebastien;Vogelgsang, Jonathan;Vyhnalek, Martin;Wagner, Michael;Wallon, David;Wang, Li-San;Wang, Ruiqi;Weinhold, Leonie;Wiltfang, Jens;Windle, Gill;Woods, Bob;Yannakoulia, Mary;Zare, Habil;Zhao, Yi;Zhang, Xiaoling;Zhu, Congcong;Zulaica, Miren;Farrer, Lindsay A.;Psaty, Bruce M.;Ghanbari, Mohsen;Raj, Towfique;Sachdev, Perminder;Mather, Karen;Jessen, Frank;Ikram, M. Arfan;de Mendonca, Alexandre;Hort, Jakub;Tsolaki, Magda;Pericak-Vance, Margaret A.;Amouyel, Philippe;Williams, Julie;Frikke-Schmidt, Ruth;Clarimon, Jordi;Deleuze, Jean-Francois;Rossi, Giacomina;Seshadri, Sudha;Andreassen, Ole A.;Ingelsson, Martin;Hiltunen, Mikko;Sleegers, Kristel;Schellenberg, Gerard D.;van Duijn, Cornelia M.;Sims, Rebecca;van der Flier, Wiesje M.;Ruiz, Agustin;Ramirez, Alfredo;Lambert, Jean-Charles
通讯作者：
Lambert, Jean-Charles
影响因子：
3.5
作者：
Bras J;Guerreiro R;Darwent L;Parkkinen L;Ansorge O;Escott-Price V;Hernandez DG;Nalls MA;Clark LN;Honig LS;Marder K;Van Der Flier WM;Lemstra A;Scheltens P;Rogaeva E;St George-Hyslop P;Londos E;Zetterberg H;Ortega-Cubero S;Pastor P;Ferman TJ;Graff-Radford NR;Ross OA;Barber I;Braae A;Brown K;Morgan K;Maetzler W;Berg D;Troakes C;Al-Sarraj S;Lashley T;Compta Y;Revesz T;Lees A;Cairns N;Halliday GM;Mann D;Pickering-Brown S;Dickson DW;Singleton A;Hardy J
通讯作者：
Hardy J
影响因子：
30.8
作者：
Chia R;Sabir MS;Bandres-Ciga S;Saez-Atienzar S;Reynolds RH;Gustavsson E;Walton RL;Ahmed S;Viollet C;Ding J;Makarious MB;Diez-Fairen M;Portley MK;Shah Z;Abramzon Y;Hernandez DG;Blauwendraat C;Stone DJ;Eicher J;Parkkinen L;Ansorge O;Clark L;Honig LS;Marder K;Lemstra A;St George-Hyslop P;Londos E;Morgan K;Lashley T;Warner TT;Jaunmuktane Z;Galasko D;Santana I;Tienari PJ;Myllykangas L;Oinas M;Cairns NJ;Morris JC;Halliday GM;Van Deerlin VM;Trojanowski JQ;Grassano M;Calvo A;Mora G;Canosa A;Floris G;Bohannan RC;Brett F;Gan-Or Z;Geiger JT;Moore A;May P;Krüger R;Goldstein DS;Lopez G;Tayebi N;Sidransky E;American Genome Center;Norcliffe-Kaufmann L;Palma JA;Kaufmann H;Shakkottai VG;Perkins M;Newell KL;Gasser T;Schulte C;Landi F;Salvi E;Cusi D;Masliah E;Kim RC;Caraway CA;Monuki ES;Brunetti M;Dawson TM;Rosenthal LS;Albert MS;Pletnikova O;Troncoso JC;Flanagan ME;Mao Q;Bigio EH;Rodríguez-Rodríguez E;Infante J;Lage C;González-Aramburu I;Sanchez-Juan P;Ghetti B;Keith J;Black SE;Masellis M;Rogaeva E;Duyckaerts C;Brice A;Lesage S;Xiromerisiou G;Barrett MJ;Tilley BS;Gentleman S;Logroscino G;Serrano GE;Beach TG;McKeith IG;Thomas AJ;Attems J;Morris CM;Palmer L;Love S;Troakes C;Al-Sarraj S;Hodges AK;Aarsland D;Klein G;Kaiser SM;Woltjer R;Pastor P;Bekris LM;Leverenz JB;Besser LM;Kuzma A;Renton AE;Goate A;Bennett DA;Scherzer CR;Morris HR;Ferrari R;Albani D;Pickering-Brown S;Faber K;Kukull WA;Morenas-Rodriguez E;Lleó A;Fortea J;Alcolea D;Clarimon J;Nalls MA;Ferrucci L;Resnick SM;Tanaka T;Foroud TM;Graff-Radford NR;Wszolek ZK;Ferman T;Boeve BF;Hardy JA;Topol EJ;Torkamani A;Singleton AB;Ryten M;Dickson DW;Chiò A;Ross OA;Gibbs JR;Dalgard CL;Traynor BJ;Scholz SW
通讯作者：
Scholz SW
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G