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

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Bellenguez, Céline, Küçükali, 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, Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antúnez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Pastor, Alfonso Arias, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belén, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Céline, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Mercè, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossù, Paola, Bråthen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, KJ ORCID: https://orcid.org/0000-0003-2427-2513, Brusco, Luis Ignacio, Buiza-Rueda, Dolores, Bûrger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Geneviève, Chung, Jaeyoon, Cuccaro, Michael L., Carracedo, Ángel, Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. 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Official URL: http://doi.org/10.1038/s41588-022-01024-z

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.

Item Type:	Journal article
Publication Title:	Nature Genetics
Creators:	Bellenguez, C., Küçükali, F., Jansen, I.E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A.C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P.A., Boland, A., Damotte, V., van der Lee, S.J., Costa, M.R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J.C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N.J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A.A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A.B., Below, J.E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K.J., Brusco, L.I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W.S., Calero, M., Cantwell, L.B., Chene, G., Chung, J., Cuccaro, M.L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H.H., Chillotti, C., Ciccone, S., Claassen, J.A. .H. .R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M.C., Daniele, A., Dardiotis, E., Dartigues, J.F., de Deyn, P.P., de Paiva Lopes, K., de Witte, L.D., Debette, S., Deckert, J., del Ser, T., Denning, N., DeStefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P.D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K.M., Fabrizio, T., Nielsen, S.F., Fardo, D.W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C.B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T.M., Fostinelli, S., Fox, N.C., Franco-Macías, E., Bullido, M.J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J.M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A.M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J.L., Hamilton-Nelson, K.L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A.M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M.T., Hernández, I., Herrmann, M.J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R.H., Hulsman, M., Humphrey, J., Biessels, G.J., Jian, X., Johansson, C., Jun, G.R., Kastumata, Y., Kauwe, J., Kehoe, P.G., Kilander, L., Ståhlbom, A.K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M.H., Kukull, W.A., Kuksa, P.P., Kunkle, B.W., Kuzma, A.B., Lage, C., Laukka, E.J., Launer, L., Lauria, A., Lee, C.Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A.L., Love, S., Löwemark, 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Publisher:	Nature
Date:	April 2022
Volume:	54
Number:	4
ISSN:	1061-4036
Identifiers:	Number Type 10.1038/s41588-022-01024-z DOI
Rights:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	24 Oct 2022 10:24
Last Modified:	24 Oct 2022 10:32
URI:	https://irep.ntu.ac.uk/id/eprint/47301