DNA methylation signatures of Alzheimer's disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types.
DNA methylation signatures of Alzheimer's disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types.
复制标题
DOI：
10.1038/s41467-022-33394-7
复制
发表时间：
2022-09-24
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征在于淀粉样蛋白-β和tau的神经元缠结在新皮质中的进行性积累。我们分析了来自631名捐赠者的两个皮质区域的DNA甲基化，对AD神经病理学的多个指标进行了表观基因组关联研究。我们将我们的结果与先前AD皮质中DNA甲基化研究的结果进行荟萃分析（总n = 2013名供体），确定了334个与AD病理学相关的皮质差异甲基化位置（DMP），包括先前未涉及痴呆的基因座的甲基化变异。随后，我们分析了NeuN+（神经元富集）、SOX 10+（少突胶质细胞富集）和NeuN-/SOX 10-（小胶质细胞和星形胶质细胞富集）细胞核中的DNA甲基化，发现在"大块"皮质组织中鉴定的大多数DMP反映了非神经元细胞中发生的DNA甲基化差异。我们的研究强调了利用多种神经病理学指标来鉴定AD的表观遗传特征的能力，以及表征纯化细胞类型中疾病相关变异的重要性。在这里，作者确定了与阿尔茨海默病病理学相关的皮质DNA甲基化的差异，并分析了特定细胞类型的细胞核，发现这些差异中的大多数反映了非神经元细胞中发生的变化。
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types. Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.
登录
查看更多内容
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：
16.6
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
通讯作者：
Ruiz A
影响因子：
9.8
作者：
Göring, HHH;Terwilliger, JD;Blangero, J
通讯作者：
Blangero, J
影响因子：
30.8
作者：
Chang D;Nalls MA;Hallgrímsdóttir IB;Hunkapiller J;van der Brug M;Cai F;International Parkinson's Disease Genomics Consortium;23andMe Research Team;Kerchner GA;Ayalon G;Bingol B;Sheng M;Hinds D;Behrens TW;Singleton AB;Bhangale TR;Graham RR
通讯作者：
Graham RR
DOI：
10.3233/jad-180699
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Francis PT;Costello H;Hayes GM
通讯作者：
Hayes GM