Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
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., 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 J-S., 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 L-S., 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., 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., 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 J-C., van der Lee SJ., Ruiz A.
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.