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

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; Mart...

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Authors

Itziar de Rojas

Sonia Moreno-Grau

Niccolo Tesi

Benjamin Grenier-Boley

Victor Andrade

Iris E. Jansen

Nancy L. Pedersen

Najada Stringa

Anna Zettergren

Isabel Hernández

Laura Montrreal

Carmen Antúnez

Anna Antonell

Rick M. Tankard

Joshua C. 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 C. Naj

Afina W. Lemstra

Alba Benaque

Alba Pérez-Cordón

Alberto Benussi

Alberto Rábano

Alessandro Padovani

Alessio Squassina

Alexandre de Mendonça

Alfonso Arias Pastor

Almar A. L. Kok

Alun Meggy

Ana Belén Pastor

Ana Espinosa

Anaïs Corma-Gómez

Angel Martín Montes

Ángela Sanabria

Anita L. DeStefano

Anja Schneider

Annakaisa Haapasalo

Anne Kinhult Ståhlbom

Anne Tybjærg-Hansen

Annette M. Hartmann

Annika Spottke

Arturo Corbatón-Anchuelo

Arvid Rongve

Barbara Borroni

Beatrice Arosio

Benedetta Nacmias

Børge G. Nordestgaard

Brian W. Kunkle

Camille Charbonnier

Carla Abdelnour

Carlo Masullo

Carmen Martínez Rodríguez

Carmen Muñoz-Fernandez

Carole Dufouil

Caroline Graff

Catarina B. Ferreira

Caterina Chillotti

Chandra A. Reynolds

Chiara Fenoglio

Christine Van Broeckhoven

Christopher Clark

Claudia Pisanu

Claudia L. 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 K. 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 L. Haines

Jonathan Vogelgsang

Juan A. Pineda

Juan Fortea

Julius Popp

Jürgen Deckert

Katharina Buerger

Kevin Morgan

Klaus Fließbach

Kristel Sleegers

Laura Molina-Porcel

Lena Kilander

Leonie Weinhold

Lindsay A. 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 A. Pericak-Vance

Margaret Esiri

María Bernal Sánchez-Arjona

Maria Carolina Dalmasso

María Teresa Martínez-Larrad

Marina Arcaro

Markus M. Nöthen

Marta Fernández-Fuertes

Martin Dichgans

Martin Ingelsson

Martin J. Herrmann

Martin Scherer

Martin Vyhnalek

Mary H. Kosmidis

Mary Yannakoulia

Matthias Schmid

Michael Ewers

Michael T. Heneka

Michael Wagner

Michela Scamosci

Miia Kivipelto

Mikko Hiltunen

Miren Zulaica

Montserrat Alegret

Myriam Fornage

Natalia Roberto

Natasja M. van Schoor

Nazib M. Seidu

Nerisa Banaj

Nicola J. 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

Per Hoffmann

Peter A. Holmans

Peter Fischer

Peter Riederer

Qiong Yang

Rachel Marshall

Rajesh N. 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 A. L. 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 G. Politis

Daniel Janowitz

David Craig

David M. Mann

David Neary

Deckert Jürgen

Delphine Daian

Diyana Belezhanska

Eduardo Kohler

Eduardo M. Castaño

Effrosyni Koutsouraki

Elena Chipi

Ellen De Roeck

Emanuele Costantini

Emma R. L. C. 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 M. 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 J. Herrman

Mary H. Kosmidis

Matias Kohler

Matias Rojo

Matthew Jones

Michela Orsini

Nancy Medel

Natividad Olivar

Nick C. Fox

Nicola Salvadori

Nigel M. Hooper

Pablo Galeano

Patricia Solis

Patrizia Bastiani

Patrizia Mecocci

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 M. 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. T. Martínez

M. Marquié

A. Mauleón

L. Montrreal

S. Moreno-Grau

M. Moreno

A. Orellana

G. Ortega

A. Pancho

E. Pelejá

A. Pérez-Cordon

J. A. Pineda

S. Preckler

I. Quintela

L. M. Real

M. Rosende-Roca

A. Ruiz

M. E. Sáez

A. Sanabria

M. Serrano-Rios

O. Sotolongo-Grau

L. Tárraga

S. Valero

L. Vargas

A. D. Adarmes-Gómez

E. Alarcón-Martín

M. D. Alonso

I. Álvarez

V. Álvarez

G. Amer-Ferrer

M. Antequera

C. Antúnez

M. Baquero

M. Bernal

R. Blesa

M. Boada

D. Buiza-Rueda

M. J. Bullido

J. A. Burguera

M. Calero

F. Carrillo

M. Carrión-Claro

M. J. Casajeros

J. Clarimón

J. M. Cruz-Gamero

M. 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. M. García-Alberca

S. Garcia Madrona

G. Garcia-Ribas

P. Gómez-Garre

I. Hernández

S. Hevilla

S. Jesús

M. A. 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. L. 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. L. Royo

A. Ruiz

R. Sanchez del Valle Díaz

P. Sánchez-Juan

I. Sastre

S. Valero

M. P. Vicente

R. Vigo-Ortega

L. Vivancos

C. Macleod

C. McCracken

Carol Brayne

Catherine Bresner

Detelina Grozeva

Eftychia Bellou

Ewen W. 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 E. 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 J. Bullido

Victoria Álvarez

Alberto Lleó

Luis M. Real

Pablo Mir

Miguel Medina

Philip Scheltens

Henne Holstege

Marta Marquié

María Eugenia Sáez

Ángel Carracedo

Philippe Amouyel

Gerard D. Schellenberg

Julie Williams

Sudha Seshadri

Cornelia M. van Duijn

Karen A. Mather

Raquel Sánchez-Valle

Manuel Serrano-Ríos

Adelina Orellana

Lluís Tárraga

Kaj Blennow

Martijn Huisman

Ole A. Andreassen

Danielle Posthuma

Jordi Clarimón

Mercè Boada

Wiesje M. van der Flier

Alfredo Ramirez

Jean-Charles Lambert

Sven J. van der Lee

Agustín Ruiz

EADB contributors

The GR@ACE study group

DEGESCO consortium

IGAP (ADGC, CHARGE, EADI, GERAD)

PGC-ALZ consortia



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.

Citation

de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I. E., …PGC-ALZ consortia. (2021). Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nature Communications, 12(1), Article 3417. https://doi.org/10.1038/s41467-021-22491-8

Journal Article Type Article
Acceptance Date Mar 17, 2021
Online Publication Date Jun 7, 2021
Publication Date Jun 7, 2021
Deposit Date Jun 14, 2021
Publicly Available Date Jun 14, 2021
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 12
Issue 1
Article Number 3417
DOI https://doi.org/10.1038/s41467-021-22491-8
Keywords General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
Public URL https://nottingham-repository.worktribe.com/output/5670496
Publisher URL https://www.nature.com/articles/s41467-021-22491-8

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