Humphrey Lab

Genetics of Neurodegeneration

New insights into the genetic etiology of Alzheimer’s disease and related dementias


Journal article


C. Bellenguez, Fahri Küçükali, I. Jansen, L. Kleineidam, S. Moreno-Grau, N. Amin, A. Naj, Rafael Campos-Martin, B. Grenier‐Boley, V. Andrade, P. Holmans, A. Boland, V. Damotte, S. J. van der Lee, M. R. Costa, T. Kuulasmaa, Qiong Yang, I. de Rojas, J. Bis, A. Yaqub, I. Prokić, J. Chapuis, S. Ahmad, V. Giedraitis, D. Aarsland, P. García-González, C. Abdelnour, E. Alarcón‐Martín, D. Alcolea, M. Alegret, I. Álvarez, V. Álvarez, N. Armstrong, A. Tsolaki, C. Antunez, I. Appollonio, M. Arcaro, S. Archetti, A. Pastor, B. Arosio, L. Athanasiu, H. Bailly, N. Banaj, M. Baquero, S. Barral, A. Beiser, A. Pastor, J. Below, Penelope H. Benchek, L. Benussi, C. Berr, C. Besse, Valentina Bessi, G. Binetti, Alessandra Bizarro, R. Blesa, M. Boada, E. Boerwinkle, B. Borroni, S. Boschi, P. Bossù, G. Bråthen, J. Bressler, Catherine Bresner, H. Brodaty, K. Brookes, L. Brusco, D. Buiza‐Rueda, K. Bûrger, V. Burholt, W. Bush, M. Calero, L. Cantwell, G. Chêne, Jaeyoon Chung, M. Cuccaro, Á. Carracedo, R. Cecchetti, Laura Cervera-Carles, C. Charbonnier, Hung-Hsin Chen, C. Chillotti, S. Ciccone, J. Claassen, C. Clark, E. Conti, A. Corma-Gómez, E. Costantini, C. Custodero, D. Daian, M. C. Dalmasso, A. Daniele, E. Dardiotis, J. Dartigues, P. D. de Deyn, Katia de Paiva Lopes, L. D. de Witte, S. Debette, J. Deckert, T. del Ser, N. Denning, A. Destefano, M. Dichgans, J. Diehl-Schmid, M. Diez-Fairen, P. Rossi, S. Djurovic, E. Duron, E. Düzel, C. Dufouil, G. Eiriksdottir, S. Engelborghs, V. Escott-Price, A. Espinosa, M. Ewers, K. Faber, Tagliavini Fabrizio, S. F. Nielsen, D. Fardo, L. Farotti, C. Fenoglio, M. Fernandez-Fuertes, R. Ferrari, Catarina B. Ferreira, E. Ferri, B. Fin, P. Fischer, T. Fladby, K. Fliessbach, Bernard Fongang, M. Fornage, J. Fortea, T. Foroud, Silvia Fostinelli, Nick C Fox, E. Franco-Macías, M. Bullido, A. Frank‐García, L. Froelich, B. Fulton-Howard, D. Galimberti, J. M. García-Alberca, P. García-González, S. García-Madrona, G. García-Ribas, R. Ghidoni, I. Giegling, Giaccone Giorgio, A. Goate, O. Goldhardt, Duber Gomez-Fonseca, A. Gonzáléz-Pérez, C. Graff, G. Grande, E. Green, T. Grimmer, E. Grünblatt, M. Grunin, V. Gudnason, Tamar Guetta‐Baranés, A. Haapasalo, G. Hadjigeorgiou, J. Haines, K. Hamilton-Nelson, H. Hampel, O. Hanon, J. Hardy, A. Hartmann, L. Hausner, J. Harwood, S. Heilmann-Heimbach, S. Helisalmi, M. Heneka, I. Hernández, M. Herrmann, P. Hoffmann, C. Holmes, H. Holstege, Raquel Huerto Vilas, M. Hulsman, J. Humphrey, G. Biessels, X. Jian, C. Johansson, G. Jun, Y. Kastumata, J. Kauwe, P. Kehoe, L. Kilander, A. Ståhlbom, M. Kivipelto, A. Koivisto, J. Kornhuber, M. Kosmidis, W. Kukull, Pavel P. Kuksa, B. Kunkle, A. Kuzma, C. Lage, E. Laukka, L. Launer, A. Lauria, Chien-Yueh Lee, J. Lehtisalo, O. Lerch, A. Lleó, W. Longstreth, O. Lopez, A. L. de Munain, S. Love, Malin Löwemark, L. Luckcuck, K. Lunetta, Yiyi Ma, J. Macías, C. MacLeod, W. Maier, F. Mangialasche, M. Spallazzi, M. Marquié, R. Marshall, E. R. Martin, Angel Martin Montes, Carmen Martínez Rodríguez, C. Masullo, R. Mayeux, S. Mead, P. Mecocci, M. Medina, A. Meggy, S. Mehrabian, S. Mendoza, M. Menéndez-González, P. Mir, S. Moebus, M. Mol, L. Molina-Porcel, L. Montrreal, L. Morelli, F. Moreno, K. Morgan, T. Mosley, M. Nöthen, C. Muchnik, S. Mukherjee, B. Nacmias, T. Ngandu, G. Nicolas, B. Nordestgaard, R. Olaso, A. Orellana, Michela Orsini, G. Ortega, A. Padovani, Caffarra Paolo, G. Papenberg, L. Parnetti, F. Pasquier, P. Pastor, G. Peloso, A. Pérez-Cordón, J. Pérez-Tur, Pierre Pericard, O. Peters, Y. Pijnenburg, J. Pineda, G. Piñol-Ripoll, C. Pisanu, T. Polak, J. Popp, D. Posthuma, J. Priller, R. Puerta, O. Quenez, I. Quintela, J. Thomassen, A. Rábano, I. Rainero, F. Rajabli, I. Ramakers, L. Real, M. Reinders, C. Reitz, D. Reyes-Dumeyer, P. Ridge, S. Riedel-Heller, P. Riederer, N. Roberto, E. Rodríguez-Rodríguez, A. Rongve, I. Allende, M. Rosende-Roca, J. Royo, E. Rubino, D. Rujescu, M. Sáez, P. Sakka, I. Saltvedt, Á. Sanabria, M. B. Sánchez-Arjona, F. Sánchez-García, P. S. Juan, R. Sánchez-Valle, S. Sando, C. Sarnowski, C. Satizabal, M. Scamosci, N. Scarmeas, E. Scarpini, P. Scheltens, N. Scherbaum, M. Scherer, M. Schmid, A. Schneider, J. Schott, G. Selbæk, D. Seripa, M. Serrano, Jin Sha, A. Shadrin, O. Skrobot, S. Slifer, G. Snijders, H. Soininen, V. Solfrizzi, A. Solomon, Yeunjoo E. Song, S. Sorbi, O. Sotolongo-Grau, G. Spalletta, A. Spottke, A. Squassina, E. Stordal, Juan Pablo Tartan, L. Tárraga, N. Tesi, A. Thalamuthu, Tegos Thomas, G. Tosto, L. Traykov, L. Tremolizzo, A. Tybjærg-Hansen, A. Uitterlinden, Abbe Ullgren, I. Ulstein, S. Valero, O. Valladares, C. Broeckhoven, J. Vance, B. Vardarajan, A. van der Lugt, Jasper Van Dongen, Jeroen G J van Rooij, J. V. van Swieten, R. Vandenberghe, F. Verhey, J. Vidal, Jonathan S. Vogelgsang, M. Vyhnálek, Michael Wagner, D. Wallon, Li-San Wang, Ruiqi Wang, L. Weinhold, J. Wiltfang, Gill Windle, B. Woods, M. Yannakoulia, Habil Zare, Yi Zhao, Xiaoling Zhang, Congcong Zhu, M. Zulaica, L. Farrer, B. Psaty, M. Ghanbari, T. Raj, P. Sachdev, K. Mather, F. Jessen, M. A. Ikram, A. de Mendonça, J. Hort, M. Tsolaki, M. Pericak-Vance, P. Amouyel, Julie Williams, R. Frikke-Schmidt, J. Clarimón, J. Deleuze, G. Rossi, S. Seshadri, O. Andreassen, M. Ingelsson, M. Hiltunen, K. Sleegers, G. Schellenberg, C. V. van Duijn, R. Sims, W. M. van der Flier, A. Ruiz, A. Ramírez, J. Lambert
Nature Genetics, 2022

Semantic Scholar DOI
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APA   Click to copy
Bellenguez, C., Küçükali, F., Jansen, I., Kleineidam, L., Moreno-Grau, S., Amin, N., … Lambert, J. (2022). New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics.


Chicago/Turabian   Click to copy
Bellenguez, C., Fahri Küçükali, I. Jansen, L. Kleineidam, S. Moreno-Grau, N. Amin, A. Naj, et al. “New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias.” Nature Genetics (2022).


MLA   Click to copy
Bellenguez, C., et al. “New Insights into the Genetic Etiology of Alzheimer’s Disease and Related Dementias.” Nature Genetics, 2022.


BibTeX   Click to copy

@article{c2022a,
  title = {New insights into the genetic etiology of Alzheimer’s disease and related dementias},
  year = {2022},
  journal = {Nature Genetics},
  author = {Bellenguez, C. and Küçükali, Fahri and Jansen, I. and Kleineidam, L. and Moreno-Grau, S. and Amin, N. and Naj, A. and Campos-Martin, Rafael and Grenier‐Boley, B. and Andrade, V. and Holmans, P. and Boland, A. and Damotte, V. and van der Lee, S. J. and Costa, M. R. and Kuulasmaa, T. and Yang, Qiong and de Rojas, I. and Bis, J. and Yaqub, A. and Prokić, I. and Chapuis, J. and Ahmad, S. and Giedraitis, V. and Aarsland, D. and García-González, P. and Abdelnour, C. and Alarcón‐Martín, E. and Alcolea, D. and Alegret, M. and Álvarez, I. and Álvarez, V. and Armstrong, N. and Tsolaki, A. and Antunez, C. and Appollonio, I. and Arcaro, M. and Archetti, S. and Pastor, A. and Arosio, B. and Athanasiu, L. and Bailly, H. and Banaj, N. and Baquero, M. and Barral, S. and Beiser, A. and Pastor, A. and Below, J. and Benchek, Penelope H. and Benussi, L. and Berr, C. and Besse, C. and Bessi, Valentina and Binetti, G. and Bizarro, Alessandra and Blesa, R. and Boada, M. and Boerwinkle, E. and Borroni, B. and Boschi, S. and Bossù, P. and Bråthen, G. and Bressler, J. and Bresner, Catherine and Brodaty, H. and Brookes, K. and Brusco, L. and Buiza‐Rueda, D. and Bûrger, K. and Burholt, V. and Bush, W. and Calero, M. and Cantwell, L. and Chêne, G. and Chung, Jaeyoon and Cuccaro, M. and Carracedo, Á. and Cecchetti, R. and Cervera-Carles, Laura and Charbonnier, C. and Chen, Hung-Hsin and Chillotti, C. and Ciccone, S. and Claassen, J. and Clark, C. and Conti, E. and Corma-Gómez, A. and Costantini, E. and Custodero, C. and Daian, D. and Dalmasso, M. C. and Daniele, A. and Dardiotis, E. and Dartigues, J. and de Deyn, P. D. and de Paiva Lopes, Katia and de Witte, L. D. and Debette, S. and Deckert, J. and del Ser, T. and Denning, N. and Destefano, A. and Dichgans, M. and Diehl-Schmid, J. and Diez-Fairen, M. and Rossi, P. and Djurovic, S. and Duron, E. and Düzel, E. and Dufouil, C. and Eiriksdottir, G. and Engelborghs, S. and Escott-Price, V. and Espinosa, A. and Ewers, M. and Faber, K. and Fabrizio, Tagliavini and Nielsen, S. F. and Fardo, D. and Farotti, L. and Fenoglio, C. and Fernandez-Fuertes, M. and Ferrari, R. and Ferreira, Catarina B. and Ferri, E. and Fin, B. and Fischer, P. and Fladby, T. and Fliessbach, K. and Fongang, Bernard and Fornage, M. and Fortea, J. and Foroud, T. and Fostinelli, Silvia and Fox, Nick C and Franco-Macías, E. and Bullido, M. and Frank‐García, A. and Froelich, L. and Fulton-Howard, B. and Galimberti, D. and García-Alberca, J. M. and García-González, P. and García-Madrona, S. and García-Ribas, G. and Ghidoni, R. and Giegling, I. and Giorgio, Giaccone and Goate, A. and Goldhardt, O. and Gomez-Fonseca, Duber and Gonzáléz-Pérez, A. and Graff, C. and Grande, G. and Green, E. and Grimmer, T. and Grünblatt, E. and Grunin, M. and Gudnason, V. and Guetta‐Baranés, Tamar and Haapasalo, A. and Hadjigeorgiou, G. and Haines, J. and Hamilton-Nelson, K. and Hampel, H. and Hanon, O. and Hardy, J. and Hartmann, A. and Hausner, L. and Harwood, J. and Heilmann-Heimbach, S. and Helisalmi, S. and Heneka, M. and Hernández, I. and Herrmann, M. and Hoffmann, P. and Holmes, C. and Holstege, H. and Vilas, Raquel Huerto and Hulsman, M. and Humphrey, J. and Biessels, G. and Jian, X. and Johansson, C. and Jun, G. and Kastumata, Y. and Kauwe, J. and Kehoe, P. and Kilander, L. and Ståhlbom, A. and Kivipelto, M. and Koivisto, A. and Kornhuber, J. and Kosmidis, M. and Kukull, W. and Kuksa, Pavel P. and Kunkle, B. and Kuzma, A. and Lage, C. and Laukka, E. and Launer, L. and Lauria, A. and Lee, Chien-Yueh and Lehtisalo, J. and Lerch, O. and Lleó, A. and Longstreth, W. and Lopez, O. and de Munain, A. L. and Love, S. and Löwemark, Malin and Luckcuck, L. and Lunetta, K. and Ma, Yiyi and Macías, J. and MacLeod, C. and Maier, W. and Mangialasche, F. and Spallazzi, M. and Marquié, M. and Marshall, R. and Martin, E. R. and Montes, Angel Martin and Rodríguez, Carmen Martínez and Masullo, C. and Mayeux, R. and Mead, S. and Mecocci, P. and Medina, M. and Meggy, A. and Mehrabian, S. and Mendoza, S. and Menéndez-González, M. and Mir, P. and Moebus, S. and Mol, M. and Molina-Porcel, L. and Montrreal, L. and Morelli, L. and Moreno, F. and Morgan, K. and Mosley, T. and Nöthen, M. and Muchnik, C. and Mukherjee, S. and Nacmias, B. and Ngandu, T. and Nicolas, G. and Nordestgaard, B. and Olaso, R. and Orellana, A. and Orsini, Michela and Ortega, G. and Padovani, A. and Paolo, Caffarra and Papenberg, G. and Parnetti, L. and Pasquier, F. and Pastor, P. and Peloso, G. and Pérez-Cordón, A. and Pérez-Tur, J. and Pericard, Pierre and Peters, O. and Pijnenburg, Y. and Pineda, J. and Piñol-Ripoll, G. and Pisanu, C. and Polak, T. and Popp, J. and Posthuma, D. and Priller, J. and Puerta, R. and Quenez, O. and Quintela, I. and Thomassen, J. and Rábano, A. and Rainero, I. and Rajabli, F. and Ramakers, I. and Real, L. and Reinders, M. and Reitz, C. and Reyes-Dumeyer, D. and Ridge, P. and Riedel-Heller, S. and Riederer, P. and Roberto, N. and Rodríguez-Rodríguez, E. and Rongve, A. and Allende, I. and Rosende-Roca, M. and Royo, J. and Rubino, E. and Rujescu, D. and Sáez, M. and Sakka, P. and Saltvedt, I. and Sanabria, Á. and Sánchez-Arjona, M. B. and Sánchez-García, F. and Juan, P. S. and Sánchez-Valle, R. and Sando, S. and Sarnowski, C. and Satizabal, C. and Scamosci, M. and Scarmeas, N. and Scarpini, E. and Scheltens, P. and Scherbaum, N. and Scherer, M. and Schmid, M. and Schneider, A. and Schott, J. and Selbæk, G. and Seripa, D. and Serrano, M. and Sha, Jin and Shadrin, A. and Skrobot, O. and Slifer, S. and Snijders, G. and Soininen, H. and Solfrizzi, V. and Solomon, A. and Song, Yeunjoo E. and Sorbi, S. and Sotolongo-Grau, O. and Spalletta, G. and Spottke, A. and Squassina, A. and Stordal, E. and Tartan, Juan Pablo and Tárraga, L. and Tesi, N. and Thalamuthu, A. and Thomas, Tegos and Tosto, G. and Traykov, L. and Tremolizzo, L. and Tybjærg-Hansen, A. and Uitterlinden, A. and Ullgren, Abbe and Ulstein, I. and Valero, S. and Valladares, O. and Broeckhoven, C. and Vance, J. and Vardarajan, B. and van der Lugt, A. and Dongen, Jasper Van and van Rooij, Jeroen G J and van Swieten, J. V. and Vandenberghe, R. and Verhey, F. and Vidal, J. and Vogelgsang, Jonathan S. and Vyhnálek, M. and Wagner, Michael and Wallon, D. and Wang, Li-San and Wang, Ruiqi and Weinhold, L. and Wiltfang, J. and Windle, Gill and Woods, B. and Yannakoulia, M. and Zare, Habil and Zhao, Yi and Zhang, Xiaoling and Zhu, Congcong and Zulaica, M. and Farrer, L. and Psaty, B. and Ghanbari, M. and Raj, T. and Sachdev, P. and Mather, K. and Jessen, F. and Ikram, M. A. and de Mendonça, A. and Hort, J. and Tsolaki, M. and Pericak-Vance, M. and Amouyel, P. and Williams, Julie and Frikke-Schmidt, R. and Clarimón, J. and Deleuze, J. and Rossi, G. and Seshadri, S. and Andreassen, O. and Ingelsson, M. and Hiltunen, M. and Sleegers, K. and Schellenberg, G. and van Duijn, C. V. and Sims, R. and van der Flier, W. M. and Ruiz, A. and Ramírez, A. and Lambert, J.}
}

Abstract

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.


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