Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Authors: de Rojas Itziar , Moreno-Grau Sonia , Tesi Niccolo , Grenier-Boley Benjamin , Andrade Victor , Jansen Iris E. , Pedersen Nancy L. , Stringa Najada , Zettergren Anna , Hernández Isabel , Montrreal Laura , Antúnez Carmen , Antonell Anna , Tankard Rick M. , Bis Joshua C. , Sims Rebecca , Bellenguez Céline , Quintela Inés , González-Perez Antonio , Calero Miguel , Franco-Macías Emilio , Macías Juan , Blesa Rafael , Cervera-Carles Laura , Menéndez-González Manuel , Frank-García Ana , Royo Jose Luís , Moreno Fermin , Huerto Vilas Raquel , Baquero Miquel , Diez-Fairen Mónica , Lage Carmen , García-Madrona Sebastián , García-González Pablo , Alarcón-Martín Emilio , Valero Sergi , Sotolongo-Grau Oscar , Ullgren Abbe , Naj Adam C. , Lemstra Afina W. , Benaque Alba , Pérez-Cordón Alba , Benussi Alberto , Rábano Alberto , Padovani Alessandro , Squassina Alessio , de Mendonça Alexandre , Arias Pastor Alfonso , Kok Almar A. L. , Meggy Alun , Pastor Ana Belén , Espinosa Ana , Corma-Gómez Anaïs , Martín Montes Angel , Sanabria Ángela , DeStefano Anita L. , Schneider Anja , Haapasalo Annakaisa , Kinhult Ståhlbom Anne , Tybjærg-Hansen Anne , Hartmann Annette M. , Spottke Annika , Corbatón-Anchuelo Arturo , Rongve Arvid , Borroni Barbara , Arosio Beatrice , Nacmias Benedetta , Nordestgaard Børge G. , Kunkle Brian W. , Charbonnier Camille , Abdelnour Carla , Masullo Carlo , Martínez Rodríguez Carmen , Muñoz-Fernandez Carmen , Dufouil Carole , Graff Caroline , Ferreira Catarina B. , Chillotti Caterina , Reynolds Chandra A. , Fenoglio Chiara , Van Broeckhoven Christine , Clark Christopher , Pisanu Claudia , Satizabal Claudia L. , Holmes Clive , Buiza-Rueda Dolores , Aarsland Dag , Rujescu Dan , Alcolea Daniel , Galimberti Daniela , Wallon David , Seripa Davide , Grünblatt Edna , Dardiotis Efthimios , Düzel Emrah , Scarpini Elio , Conti Elisa , Rubino Elisa , Gelpi Ellen , Rodriguez-Rodriguez Eloy , Duron Emmanuelle , Boerwinkle Eric , Ferri Evelyn , Tagliavini Fabrizio , Küçükali Fahri , Pasquier Florence , Sanchez-Garcia Florentino , Mangialasche Francesca , Jessen Frank , Nicolas Gaël , Selbæk Geir , Ortega Gemma , Chêne Geneviève , Hadjigeorgiou Georgios , Rossi Giacomina , Spalletta Gianfranco , Giaccone Giorgio , Grande Giulia , Binetti Giuliano , Papenberg Goran , Hampel Harald , Bailly Henri , Zetterberg Henrik , Soininen Hilkka , Karlsson Ida K. , Alvarez Ignacio , Appollonio Ildebrando , Giegling Ina , Skoog Ingmar , Saltvedt Ingvild , Rainero Innocenzo , Rosas Allende Irene , Hort Jakub , Diehl-Schmid Janine , Van Dongen Jasper , Vidal Jean-Sebastien , Lehtisalo Jenni , Wiltfang Jens , Thomassen Jesper Qvist , Kornhuber Johannes , Haines Jonathan L. , Vogelgsang Jonathan , Pineda Juan A. , Fortea Juan , Popp Julius , Deckert Jürgen , Buerger Katharina , Morgan Kevin , Fließbach Klaus , Sleegers Kristel , Molina-Porcel Laura , Kilander Lena , Weinhold Leonie , Farrer Lindsay A. , Wang Li-San , Kleineidam Luca , Farotti Lucia , Parnetti Lucilla , Tremolizzo Lucio , Hausner Lucrezia , Benussi Luisa , Froelich Lutz , Ikram M. Arfan , Deniz-Naranjo M. Candida , Tsolaki Magda , Rosende-Roca Maitée , Löwenmark Malin , Hulsman Marc , Spallazzi Marco , Pericak-Vance Margaret A. , Esiri Margaret , Bernal Sánchez-Arjona María , Dalmasso Maria Carolina , Martínez-Larrad María Teresa , Arcaro Marina , Nöthen Markus M. , Fernández-Fuertes Marta , Dichgans Martin , Ingelsson Martin , Herrmann Martin J. , Scherer Martin , Vyhnalek Martin , Kosmidis Mary H. , Yannakoulia Mary , Schmid Matthias , Ewers Michael , Heneka Michael T. , Wagner Michael , Scamosci Michela , Kivipelto Miia , Hiltunen Mikko , Zulaica Miren , Alegret Montserrat , Fornage Myriam , Roberto Natalia , van Schoor Natasja M. , Seidu Nazib M. , Banaj Nerisa , Armstrong Nicola J. , Scarmeas Nikolaos , Scherbaum Norbert , Goldhardt Oliver , Hanon Oliver , Peters Oliver , Skrobot Olivia Anna , Quenez Olivier , Lerch Ondrej , Bossù Paola , Caffarra Paolo , Dionigi Rossi Paolo , Sakka Paraskevi , Mecocci Patrizia , Hoffmann Per , Holmans Peter A. , Fischer Peter , Riederer Peter , Yang Qiong , Marshall Rachel , Kalaria Rajesh N. , Mayeux Richard , Vandenberghe Rik , Cecchetti Roberta , Ghidoni Roberta , Frikke-Schmidt Ruth , Sorbi Sandro , Hägg Sara , Engelborghs Sebastiaan , Helisalmi Seppo , Botne Sando Sigrid , Kern Silke , Archetti Silvana , Boschi Silvia , Fostinelli Silvia , Gil Silvia , Mendoza Silvia , Mead Simon , Ciccone Simona , Djurovic Srdjan , Heilmann-Heimbach Stefanie , Riedel-Heller Steffi , Kuulasmaa Teemu , del Ser Teodoro , Lebouvier Thibaud , Polak Thomas , Ngandu Tiia , Grimmer Timo , Bessi Valentina , Escott-Price Valentina , Giedraitis Vilmantas , Deramecourt Vincent , Maier Wolfgang , Jian Xueqiu , Pijnenburg Yolande A. L. ,   EADB contributors, Smith A. David , Saenz Aldo , Bizzarro Alessandra , Lauria Alessandra , Vacca Alessandro , Solomon Alina , Anastasiou Anna , Richardson Anna , Boland Anne , Koivisto Anne , Daniele Antonio , Greco Antonio , Marianthi Arnaoutoglou , McGuinness Bernadette , Fin Bertrand , Ferrari Camilla , Custodero Carlo , Ferrarese Carlo , Ingino Carlos , Mangone Carlos , Reyes Toso Carlos , Martínez Carmen , Cuesta Carolina , Muchnik Carolina , Joachim Catharine , Ortiz Cecilia , Besse Céline , Johansson Charlotte , Zoia Chiara Paola , Laske Christoph , Anastasiou Costas , Palacio Dana Lis , Politis Daniel G. , Janowitz Daniel , Craig David , Mann David M. , Neary David , Jürgen Deckert , Daian Delphine , Belezhanska Diyana , Kohler Eduardo , Castaño Eduardo M. , Koutsouraki Effrosyni , Chipi Elena , De Roeck Ellen , Costantini Emanuele , Vardy Emma R. L. C. , Piras Fabrizio , Roveta Fausto , Piras Federica , Prestia Federico Ariel , Assogna Francesca , Salani Francesca , Sala Gessica , Lacidogna Giordano , Novack Gisela , Wilcock Gordon , Thonberg Håkan , Kölsch Heike , Weber Heike , Boecker Henning , Etchepareborda Ignacio , Piaceri Irene , Tuomilehto Jaakko , Lindström Jaana , Laczo Jan , Johnston Janet , Deleuze Jean-François , Harris Jenny , Schott Jonathan M. , Priller Josef , Bacha Juan Ignacio , Snowden Julie , Lisso Julieta , Mihova Kalina Yonkova , Traykov Latchezar , Morelli Laura , Brusco Luis Ignacio , Rainer Malik , Takalo Mari , Bjerke Maria , Del Zompo Maria , Serpente Maria , Sanchez Abalos Mariana , Rios Mario , Peltonen Markku , Herrman Martin J. , Kosmidis Mary H. , Kohler Matias , Rojo Matias , Jones Matthew , Orsini Michela , Medel Nancy , Olivar Natividad , Fox Nick C. , Salvadori Nicola , Hooper Nigel M. , Galeano Pablo , Solis Patricia , Bastiani Patrizia , Passmore Peter , Heun Reinhard , Antikainen Riitta , Olaso Robert , Perneczky Robert , Germani Sandra , López-García Sara , Love Seth , Mehrabian Shima , Bagnoli Silvia , Kochen Silvia , Andreoni Simona , Teipel Stefan , Todd Stephen , Pickering-Brown Stuart , Natunen Teemu , Tegos Thomas , Laatikainen Tiina , Strandberg Timo , Polvikoski Tuomo M. , Matoska Vaclav , Ciullo Valentina , Cores Valeria , Solfrizzi Vincenzo , Lisetti Viviana , Sevillano Zulma ,   The GR@ACE study group, Abdelnour C. , Aguilera N. , Alarcon E. , Alegret M. , Benaque A. , Boada M. , Buendia M. , Cañabate P. , Carracedo A. , Corbatón-Anchuelo A. , de Rojas I. , Diego S. , Espinosa A. , Gailhajenet A. , García-González P. , Gil S. , Guitart M. , González-Pérez A. , Hernández I. , Ibarria M. , Lafuente A. , Macias J. , Maroñas O. , Martín E. , Martínez M. T. , Marquié M. , Mauleón A. , Montrreal L. , Moreno-Grau S. , Moreno M. , Orellana A. , Ortega G. , Pancho A. , Pelejá E. , Pérez-Cordon A. , Pineda J. A. , Preckler S. , Quintela I. , Real L. M. , Rosende-Roca M. , Ruiz A. , Sáez M. E. , Sanabria A. , Serrano-Rios M. , Sotolongo-Grau O. , Tárraga L. , Valero S. , Vargas L. ,   DEGESCO consortium, Adarmes-Gómez A. D. , Alarcón-Martín E. , Alonso M. D. , Álvarez I. , Álvarez V. , Amer-Ferrer G. , Antequera M. , Antúnez C. , Baquero M. , Bernal M. , Blesa R. , Boada M. , Buiza-Rueda D. , Bullido M. J. , Burguera J. A. , Calero M. , Carrillo F. , Carrión-Claro M. , Casajeros M. J. , Clarimón J. , Cruz-Gamero J. M. , de Pancorbo M. M. , de Rojas I. , del Ser T. , Diez-Fairen M. , Escuela R. , Garrote-Espina L. , Fortea J. , Franco-Macías E. , Frank-García A. , García-Alberca J. M. , Garcia Madrona S. , Garcia-Ribas G. , Gómez-Garre P. , Hernández I. , Hevilla S. , Jesús S. , Labrador Espinosa M. A. , Lage C. , Legaz A. , Lleó A. , Lopez de Munain A. , López-García S. , Macias-García D. , Manzanares S. , Marín M. , Marín-Muñoz J. , Marín T. , Marquié M. , Martín Montes A. , Martínez B. , Martínez C. , Martínez V. , Martínez-Lage Álvarez P. , Medina M. , Mendioroz Iriarte M. , Menéndez-González M. , Mir P. , Molinuevo J. L. , Pastor P. , Pérez Tur J. , Periñán-Tocino T. , Pineda-Sanchez R. , Piñol-Ripoll G. , Rábano A. , Real de Asúa D. , Rodrigo S. , Rodríguez-Rodríguez E. , Royo J. L. , Ruiz A. , Sanchez del Valle Díaz R. , Sánchez-Juan P. , Sastre I. , Valero S. , Vicente M. P. , Vigo-Ortega R. , Vivancos L. ,   IGAP (ADGC, CHARGE, EADI, GERAD), Macleod C. , McCracken C. , Brayne Carol , Bresner Catherine , Grozeva Detelina , Bellou Eftychia , Sommerville Ewen W. , Matthews F. , Leonenko Ganna , Menzies Georgina , Windle Gill , Harwood Janet , Phillips Judith , Bennett K. , Luckuck Lauren , Clare Linda , Woods Robert , Saad Salha , Burholt Vanessa ,   PGC-ALZ consortia, Jansen Iris E. , Rongve Arvid , Kehoe Patrick Gavin , Garcia-Ribas Guillermo , Sánchez-Juan Pascual , Pastor Pau , Pérez-Tur Jordi , Piñol-Ripoll Gerard , Lopez de Munain Adolfo , García-Alberca Jose María , Bullido María J. , Álvarez Victoria , Lleó Alberto , Real Luis M. , Mir Pablo , Medina Miguel , Scheltens Philip , Holstege Henne , Marquié Marta , Sáez María Eugenia , Carracedo Ángel , Amouyel Philippe , Schellenberg Gerard D. , Williams Julie , Seshadri Sudha , van Duijn Cornelia M. , Mather Karen A. , Sánchez-Valle Raquel , Serrano-Ríos Manuel , Orellana Adelina , Tárraga Lluís , Blennow Kaj , Huisman Martijn , Andreassen Ole A. , Posthuma Danielle , Clarimón Jordi , Boada Mercè , van der Flier Wiesje M. , Ramirez Alfredo , Lambert Jean-Charles , van der Lee Sven J. , Ruiz Agustín 
Published: June 2021

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.