New insights into the genetic etiology of Alzheimer's disease and related dementias.
Bellenguez C., Küçükali F., Jansen IE., Kleineidam L., Moreno-Grau S., Amin N., Naj AC., Campos-Martin R., Grenier-Boley B., Andrade V., Holmans PA., Boland A., Damotte V., van der Lee SJ., Costa MR., Kuulasmaa T., Yang Q., de Rojas I., Bis JC., 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 NJ., Tsolaki A., Antúnez C., Appollonio I., Arcaro M., Archetti S., Pastor AA., Arosio B., Athanasiu L., Bailly H., Banaj N., Baquero M., Barral S., Beiser A., Pastor AB., Below JE., 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 KJ., Brusco LI., Buiza-Rueda D., Bûrger K., Burholt V., Bush WS., Calero M., Cantwell LB., Chene G., Chung J., Cuccaro ML., Carracedo Á., Cecchetti R., Cervera-Carles L., Charbonnier C., Chen H-H., Chillotti C., Ciccone S., Claassen JAHR., Clark C., Conti E., Corma-Gómez A., Costantini E., Custodero C., Daian D., Dalmasso MC., Daniele A., Dardiotis E., Dartigues J-F., de Deyn PP., de Paiva Lopes K., de Witte LD., Debette S., Deckert J., Del Ser T., Denning N., DeStefano A., Dichgans M., Diehl-Schmid J., Diez-Fairen M., Rossi PD., Djurovic S., Duron E., Düzel E., Dufouil C., Eiriksdottir G., Engelborghs S., Escott-Price V., Espinosa A., Ewers M., Faber KM., Fabrizio T., Nielsen SF., Fardo DW., Farotti L., Fenoglio C., Fernández-Fuertes M., Ferrari R., Ferreira CB., Ferri E., Fin B., Fischer P., Fladby T., Fließbach K., Fongang B., Fornage M., Fortea J., Foroud TM., Fostinelli S., Fox NC., Franco-Macías E., Bullido MJ., Frank-García A., Froelich L., Fulton-Howard B., Galimberti D., García-Alberca JM., García-González P., Garcia-Madrona S., Garcia-Ribas G., Ghidoni R., Giegling I., Giorgio G., Goate AM., 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 JL., Hamilton-Nelson KL., Hampel H., Hanon O., Hardy J., Hartmann AM., Hausner L., Harwood J., Heilmann-Heimbach S., Helisalmi S., Heneka MT., Hernández I., Herrmann MJ., Hoffmann P., Holmes C., Holstege H., Vilas RH., Hulsman M., Humphrey J., Biessels GJ., Jian X., Johansson C., Jun GR., Kastumata Y., Kauwe J., Kehoe PG., Kilander L., Ståhlbom AK., Kivipelto M., Koivisto A., Kornhuber J., Kosmidis MH., Kukull WA., Kuksa PP., Kunkle BW., Kuzma AB., Lage C., Laukka EJ., Launer L., Lauria A., Lee C-Y., Lehtisalo J., Lerch O., Lleó A., Longstreth W., Lopez O., de Munain AL., Love S., Löwemark M., Luckcuck L., Lunetta KL., Ma Y., Macías J., MacLeod CA., Maier W., Mangialasche F., Spallazzi M., Marquié M., Marshall R., Martin ER., Montes AM., Rodríguez CM., Masullo C., Mayeux R., Mead S., Mecocci P., Medina M., Meggy A., Mehrabian S., Mendoza S., Menéndez-González M., Mir P., Moebus S., Mol M., Molina-Porcel L., Montrreal L., Morelli L., Moreno F., Morgan K., Mosley T., Nöthen MM., Muchnik C., Mukherjee S., Nacmias B., Ngandu T., Nicolas G., Nordestgaard BG., Olaso R., Orellana A., Orsini M., Ortega G., Padovani A., Paolo C., Papenberg G., Parnetti L., Pasquier F., Pastor P., Peloso G., Pérez-Cordón A., Pérez-Tur J., Pericard P., Peters O., Pijnenburg YAL., Pineda JA., Piñol-Ripoll G., Pisanu C., Polak T., Popp J., Posthuma D., Priller J., Puerta R., Quenez O., Quintela I., Thomassen JQ., Rábano A., Rainero I., Rajabli F., Ramakers I., Real LM., Reinders MJT., Reitz C., Reyes-Dumeyer D., Ridge P., Riedel-Heller S., Riederer P., Roberto N., Rodriguez-Rodriguez E., Rongve A., Allende IR., Rosende-Roca M., Royo JL., Rubino E., Rujescu D., Sáez ME., Sakka P., Saltvedt I., Sanabria Á., Sánchez-Arjona MB., Sanchez-Garcia F., Juan PS., Sánchez-Valle R., Sando SB., Sarnowski C., Satizabal CL., Scamosci M., Scarmeas N., Scarpini E., Scheltens P., Scherbaum N., Scherer M., Schmid M., Schneider A., Schott JM., Selbæk G., Seripa D., Serrano M., Sha J., Shadrin AA., Skrobot O., Slifer S., Snijders GJL., Soininen H., Solfrizzi V., Solomon A., Song Y., Sorbi S., Sotolongo-Grau O., Spalletta G., Spottke A., Squassina A., Stordal E., Tartan JP., Tárraga L., Tesí N., Thalamuthu A., Thomas T., Tosto G., Traykov L., Tremolizzo L., Tybjærg-Hansen A., Uitterlinden A., Ullgren A., Ulstein I., Valero S., Valladares O., Broeckhoven CV., Vance J., Vardarajan BN., van der Lugt A., Dongen JV., van Rooij J., van Swieten J., Vandenberghe R., Verhey F., Vidal J-S., Vogelgsang J., Vyhnalek M., Wagner M., Wallon D., Wang L-S., Wang R., Weinhold L., Wiltfang J., Windle G., Woods B., Yannakoulia M., Zare H., Zhao Y., Zhang X., Zhu C., Zulaica M., EADB None., GR@ACE None., DEGESCO None., EADI None., GERAD None., Demgene None., FinnGen None., ADGC None., CHARGE None., Farrer LA., Psaty BM., Ghanbari M., Raj T., Sachdev P., Mather K., Jessen F., Ikram MA., de Mendonça A., Hort J., Tsolaki M., Pericak-Vance MA., Amouyel P., Williams J., Frikke-Schmidt R., Clarimon J., Deleuze J-F., Rossi G., Seshadri S., Andreassen OA., Ingelsson M., Hiltunen M., Sleegers K., Schellenberg GD., van Duijn CM., Sims R., van der Flier WM., Ruiz A., Ramirez A., Lambert J-C.
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.