Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Itziar de Rojas , Sonia Moreno-Grau , Niccolo Tesi , Benjamin Grenier-Boley , Victor Andrade , Iris Jansen , Nancy Pedersen , Najada Stringa , Anna Zettergren , Isabel Hernández , Laura Montrreal , Carmen Antúnez , Anna Antonell , Rick Tankard , Joshua Bis , Rebecca Sims , Céline Bellenguez , Inés Quintela , Antonio González-Perez , Miguel Calero , Emilio Franco-Macías , Juan Macías , Rafael Blesa , Laura Cervera-Carles , Manuel Menéndez-González , Ana Frank-García , Jose Luís Royo , Fermin Moreno , Raquel Huerto Vilas , Miquel Baquero , Mónica Diez-Fairen , Carmen Lage , Sebastián García-Madrona , Pablo García-González , Emilio Alarcón-Martín , Sergi Valero , Oscar Sotolongo-Grau , Abbe Ullgren , Adam Naj , Afina Lemstra , Alba Benaque , Alba Pérez-Cordón , Alberto Benussi , Alberto Rábano , Alessandro Padovani , Alessio Squassina , Alexandre de Mendonça , Alfonso Arias Pastor , Almar Kok , Alun Meggy , Ana Belén Pastor , Ana Espinosa , Anaïs Corma-Gómez , Angel Martín Montes , Ángela Sanabria , Anita Destefano , Anja Schneider , Annakaisa Haapasalo , Anne Kinhult Ståhlbom , Anne Tybjærg-Hansen , Annette Hartmann , Annika Spottke , Arturo Corbatón-Anchuelo , Arvid Rongve , Barbara Borroni , Beatrice Arosio , Benedetta Nacmias , Børge Nordestgaard , Brian Kunkle , Camille Charbonnier , Carla Abdelnour , Carlo Masullo , Carmen Martínez Rodríguez , Carmen Muñoz-Fernandez , Carole Dufouil , Caroline Graff , Catarina Ferreira , Caterina Chillotti , Chandra Reynolds , Chiara Fenoglio , Christine van Broeckhoven , Christopher Clark , Claudia Pisanu , Claudia Satizabal , Clive Holmes , Dolores Buiza-Rueda , Dag Aarsland , Dan Rujescu , Daniel Alcolea , Daniela Galimberti , David Wallon , Davide Seripa , Edna Grünblatt , Efthimios Dardiotis , Emrah Düzel , Elio Scarpini , Elisa Conti , Elisa Rubino , Ellen Gelpi , Eloy Rodriguez-Rodriguez , Emmanuelle Duron , Eric Boerwinkle , Evelyn Ferri , Fabrizio Tagliavini , Fahri Küçükali , Florence Pasquier , Florentino Sanchez-Garcia , Francesca Mangialasche , Frank Jessen , Gaël Nicolas , Geir Selbæk , Gemma Ortega , Geneviève Chêne , Georgios Hadjigeorgiou , Giacomina Rossi , Gianfranco Spalletta , Giorgio Giaccone , Giulia Grande , Giuliano Binetti , Goran Papenberg , Harald Hampel , Henri Bailly , Henrik Zetterberg , Hilkka Soininen , Ida Karlsson , Ignacio Alvarez , Ildebrando Appollonio , Ina Giegling , Ingmar Skoog , Ingvild Saltvedt , Innocenzo Rainero , Irene Rosas Allende , Jakub Hort , Janine Diehl-Schmid , Jasper van Dongen , Jean-Sebastien Vidal , Jenni Lehtisalo , Jens Wiltfang , Jesper Qvist Thomassen , Johannes Kornhuber , Jonathan Haines , Jonathan Vogelgsang , Juan Pineda , Juan Fortea , Julius Popp , Jürgen Deckert , Katharina Buerger , Kevin Morgan , Klaus Fließbach , Kristel Sleegers , Laura Molina-Porcel , Lena Kilander , Leonie Weinhold , Lindsay Farrer , Li-San Wang , Luca Kleineidam , Lucia Farotti , Lucilla Parnetti , Lucio Tremolizzo , Lucrezia Hausner , Luisa Benussi , Lutz Froelich , M. Arfan Ikram , M. Candida Deniz-Naranjo , Magda Tsolaki , Maitée Rosende-Roca , Malin Löwenmark , Marc Hulsman , Marco Spallazzi , Margaret Pericak-Vance , Margaret Esiri , María Bernal Sánchez-Arjona , Maria Carolina Dalmasso , María Teresa Martínez-Larrad , Marina Arcaro , Markus Nöthen , Marta Fernández-Fuertes , Martin Dichgans , Martin Ingelsson , Martin Herrmann , Martin Scherer , Martin Vyhnalek , Mary Kosmidis , Mary Yannakoulia , Matthias Schmid , Michael Ewers , Michael Heneka , Michael Wagner , Michela Scamosci , Miia Kivipelto , Mikko Hiltunen , Miren Zulaica , Montserrat Alegret , Myriam Fornage , Natalia Roberto , Natasja van Schoor , Nazib Seidu , Nerisa Banaj , Nicola Armstrong , Nikolaos Scarmeas , Norbert Scherbaum , Oliver Goldhardt , Oliver Hanon , Oliver Peters , Olivia Anna Skrobot , Olivier Quenez , Ondrej Lerch , Paola Bossù , Paolo Caffarra , Paolo Dionigi Rossi , Paraskevi Sakka , Patrizia Mecocci , Per Hoffmann , Peter Holmans , Peter Fischer , Peter Riederer , Qiong Yang , Rachel Marshall , Rajesh Kalaria , Richard Mayeux , Rik Vandenberghe , Roberta Cecchetti , Roberta Ghidoni , Ruth Frikke-Schmidt , Sandro Sorbi , Sara Hägg , Sebastiaan Engelborghs , Seppo Helisalmi , Sigrid Botne Sando , Silke Kern , Silvana Archetti , Silvia Boschi , Silvia Fostinelli , Silvia Gil , Silvia Mendoza , Simon Mead , Simona Ciccone , Srdjan Djurovic , Stefanie Heilmann-Heimbach , Steffi Riedel-Heller , Teemu Kuulasmaa , Teodoro del Ser , Thibaud Lebouvier , Thomas Polak , Tiia Ngandu , Timo Grimmer , Valentina Bessi , Valentina Escott-Price , Vilmantas Giedraitis , Vincent Deramecourt , Wolfgang Maier , Xueqiu Jian , Yolande Pijnenburg , A. David Smith , Aldo Saenz , Alessandra Bizzarro , Alessandra Lauria , Alessandro Vacca , Alina Solomon , Anna Anastasiou , Anna Richardson , Anne Boland , Anne Koivisto , Antonio Daniele , Antonio Greco , Arnaoutoglou Marianthi , Bernadette Mcguinness , Bertrand Fin , Camilla Ferrari , Carlo Custodero , Carlo Ferrarese , Carlos Ingino , Carlos Mangone , Carlos Reyes Toso , Carmen Martínez , Carolina Cuesta , Carolina Muchnik , Catharine Joachim , Cecilia Ortiz , Céline Besse , Charlotte Johansson , Chiara Paola Zoia , Christoph Laske , Costas Anastasiou , Dana Lis Palacio , Daniel Politis , Daniel Janowitz , David Craig , David Mann , David Neary , Deckert Jürgen , Delphine Daian , Diyana Belezhanska , Eduardo Kohler , Eduardo Castaño , Effrosyni Koutsouraki , Elena Chipi , Ellen de Roeck , Emanuele Costantini , Emma Vardy , Fabrizio Piras , Fausto Roveta , Federica Piras , Federico Ariel Prestia , Francesca Assogna , Francesca Salani , Gessica Sala , Giordano Lacidogna , Gisela Novack , Gordon Wilcock , Håkan Thonberg , Heike Kölsch , Heike Weber , Henning Boecker , Ignacio Etchepareborda , Irene Piaceri , Jaakko Tuomilehto , Jaana Lindström , Jan Laczo , Janet Johnston , Jean-François Deleuze , Jenny Harris , Jonathan Schott , Josef Priller , Juan Ignacio Bacha , Julie Snowden , Julieta Lisso , Kalina Yonkova Mihova , Latchezar Traykov , Laura Morelli , Luis Ignacio Brusco , Malik Rainer , Mari Takalo , Maria Bjerke , Maria del Zompo , Maria Serpente , Mariana Sanchez Abalos , Mario Rios , Markku Peltonen , Martin Herrman , Mary Kosmidis , Matias Kohler , Matias Rojo , Matthew Jones , Michela Orsini , Nancy Medel , Natividad Olivar , Nick Fox , Nicola Salvadori , Nigel Hooper , Pablo Galeano , Patricia Solis , Patrizia Bastiani , Peter Passmore , Reinhard Heun , Riitta Antikainen , Robert Olaso , Robert Perneczky , Sandra Germani , Sara López-García , Seth Love , Shima Mehrabian , Silvia Bagnoli , Silvia Kochen , Simona Andreoni , Stefan Teipel , Stephen Todd , Stuart Pickering-Brown , Teemu Natunen , Thomas Tegos , Tiina Laatikainen , Timo Strandberg , Tuomo Polvikoski , Vaclav Matoska , Valentina Ciullo , Valeria Cores , Vincenzo Solfrizzi , Viviana Lisetti , Zulma Sevillano , C. Abdelnour , N. Aguilera , E. Alarcon , M. Alegret , A. Benaque , M. Boada , M. Buendia , P. Cañabate , A. Carracedo , A. Corbatón-Anchuelo , I. de Rojas , S. Diego , A. Espinosa , A. Gailhajenet , P. García-González , S. Gil , M. Guitart , A. González-Pérez , I. Hernández , M. Ibarria , A. Lafuente , J. Macias , O. Maroñas , E. Martín , M. Martínez , M. Marquié , A. Mauleón , L. Montrreal , S. Moreno-Grau , M. Moreno , A. Orellana , G. Ortega , A. Pancho , E. Pelejá , A. Pérez-Cordon , J. Pineda , S. Preckler , I. Quintela , L. Real , M. Rosende-Roca , A. Ruiz , M. Sáez , A. Sanabria , M. Serrano-Rios , O. Sotolongo-Grau , L. Tárraga , S. Valero , L. Vargas , A. Adarmes-Gómez , E. Alarcón-Martín , M. Alonso , I. Álvarez , V. Álvarez , G. Amer-Ferrer , M. Antequera , C. Antúnez , M. Baquero , M. Bernal , R. Blesa , M. Boada , D. Buiza-Rueda , M. Bullido , J. Burguera , M. Calero , F. Carrillo , M. Carrión-Claro , M. Casajeros , J. Clarimón , J. Cruz-Gamero , M. de Pancorbo , I. de Rojas , T. del Ser , M. Diez-Fairen , R. Escuela , L. Garrote-Espina , J. Fortea , E. Franco-Macías , A. Frank-García , J. García-Alberca , S. Garcia Madrona , G. Garcia-Ribas , P. Gómez-Garre , I. Hernández , S. Hevilla , S. Jesús , M. Labrador Espinosa , C. Lage , A. Legaz , A. Lleó , A. Lopez de Munain , S. López-García , D. Macias-García , S. Manzanares , M. Marín , J. Marín-Muñoz , T. Marín , M. Marquié , A. Martín Montes , B. Martínez , C. Martínez , V. Martínez , P. Martínez-Lage Álvarez , M. Medina , M. Mendioroz Iriarte , M. Menéndez-González , P. Mir , J. Molinuevo , P. Pastor , J. Pérez Tur , T. Periñán-Tocino , R. Pineda-Sanchez , G. Piñol-Ripoll , A. Rábano , D. Real de Asúa , S. Rodrigo , E. Rodríguez-Rodríguez , J. Royo , A. Ruiz , R. Sanchez del Valle Díaz , P. Sánchez-Juan , I. Sastre , S. Valero , M. Vicente , R. Vigo-Ortega , L. Vivancos , C. Macleod , C. Mccracken , Carol Brayne , Catherine Bresner , Detelina Grozeva , Eftychia Bellou , Ewen Sommerville , F. Matthews , Ganna Leonenko , Georgina Menzies , Gill Windle , Janet Harwood , Judith Phillips , K. Bennett , Lauren Luckuck , Linda Clare , Robert Woods , Salha Saad , Vanessa Burholt , Iris Jansen , Arvid Rongve , Patrick Gavin Kehoe , Guillermo Garcia-Ribas , Pascual Sánchez-Juan , Pau Pastor , Jordi Pérez-Tur , Gerard Piñol-Ripoll , Adolfo Lopez de Munain , Jose María García-Alberca , María Bullido , Victoria Álvarez , Alberto Lleó , Luis Real , Pablo Mir , Miguel Medina , Philip Scheltens , Henne Holstege , Marta Marquié , María Eugenia Sáez , Ángel Carracedo , Philippe Amouyel , Gerard Schellenberg , Julie Williams , Sudha Seshadri , Cornelia van Duijn , Karen Mather , Raquel Sánchez-Valle , Manuel Serrano-Ríos , Adelina Orellana , Lluís Tárraga , Kaj Blennow , Martijn Huisman , Ole Andreassen , Danielle Posthuma , Jordi Clarimón , Mercè Boada , Wiesje van der Flier , Alfredo Ramirez , Jean-Charles Lambert (1) , Sven van der Lee , Agustín Ruiz

1 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167

Abstract 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.

Domaines: Sciences du Vivant [q-bio]

Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, et al.. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nature Communications, 2021, 12 (1), pp.3417. ⟨10.1038/s41467-021-22491-8⟩. ⟨hal-04278002⟩