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

Itziar de Rojas; Sonia Moreno-Grau; Niccolo Tesi; 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; Anne Tybjærg-Hansen; Børge G Nordestgaard; Jesper Qvist Thomassen; Michael Wagner; Ruth Frikke-Schmidt; EADB contributors

doi:10.1038/s41467-021-22491-8

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

Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, 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-MacíasJuan 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, Anne Tybjærg-Hansen, Børge G Nordestgaard, Jesper Qvist Thomassen, Michael Wagner, Ruth Frikke-Schmidt, EADB contributors

224 Citations (Scopus)

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.

Original language	English
Article number	3417
Journal	Nature Communications
Volume	12
Issue number	1
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-021-22491-8
Publication status	Published - Dec 2021

Keywords

Age of Onset
Aged
Aged, 80 and over
Alzheimer Disease/epidemiology
Amyloid beta-Protein Precursor/genetics
Apolipoproteins E/genetics
Case-Control Studies
Cohort Studies
Datasets as Topic
Female
Follow-Up Studies
Genetic Predisposition to Disease
Genome-Wide Association Study
Heterozygote
Humans
Male
Middle Aged
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Risk Assessment/methods
Risk Factors

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de Rojas, I., Moreno-Grau, S., Tesi, N., Andrade, V., Jansen, I. E., Pedersen, N. L., Stringa, N., Zettergren, A., Hernández, I., Montrreal, L., Antúnez, C., Antonell, A., Tankard, R. M., Bis, J. C., Sims, R., Bellenguez, C., Quintela, I., González-Perez, A., Calero, M., ... EADB contributors (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

de Rojas, I, Moreno-Grau, S, Tesi, N, 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, Tybjærg-Hansen, A , Nordestgaard, BG , Thomassen, JQ, Wagner, M, Frikke-Schmidt, R & EADB contributors 2021, 'Common variants in Alzheimer's disease and risk stratification by polygenic risk scores', Nature Communications, vol. 12, no. 1, 3417. https://doi.org/10.1038/s41467-021-22491-8

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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.",

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AU - de Rojas, Itziar

AU - Moreno-Grau, Sonia

AU - Tesi, Niccolo

AU - Andrade, Victor

AU - Jansen, Iris E

AU - Pedersen, Nancy L

AU - Stringa, Najada

AU - Zettergren, Anna

AU - Hernández, Isabel

AU - Montrreal, Laura

AU - Antúnez, Carmen

AU - Antonell, Anna

AU - Tankard, Rick M

AU - Bis, Joshua C

AU - Sims, Rebecca

AU - Bellenguez, Céline

AU - Quintela, Inés

AU - González-Perez, Antonio

AU - Calero, Miguel

AU - Franco-Macías, Emilio

AU - Macías, Juan

AU - Blesa, Rafael

AU - Cervera-Carles, Laura

AU - Menéndez-González, Manuel

AU - Frank-García, Ana

AU - Royo, Jose Luís

AU - Moreno, Fermin

AU - Huerto Vilas, Raquel

AU - Baquero, Miquel

AU - Diez-Fairen, Mónica

AU - Lage, Carmen

AU - García-Madrona, Sebastián

AU - García-González, Pablo

AU - Alarcón-Martín, Emilio

AU - Valero, Sergi

AU - Sotolongo-Grau, Oscar

AU - Ullgren, Abbe

AU - Naj, Adam C

AU - Lemstra, Afina W

AU - Benaque, Alba

AU - Pérez-Cordón, Alba

AU - Benussi, Alberto

AU - Rábano, Alberto

AU - Padovani, Alessandro

AU - Tybjærg-Hansen, Anne

AU - Nordestgaard, Børge G

AU - Thomassen, Jesper Qvist

AU - Wagner, Michael

AU - Frikke-Schmidt, Ruth

AU - EADB contributors

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N2 - 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.

AB - 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.

KW - Age of Onset

KW - Aged

KW - Aged, 80 and over

KW - Alzheimer Disease/epidemiology

KW - Amyloid beta-Protein Precursor/genetics

KW - Apolipoproteins E/genetics

KW - Case-Control Studies

KW - Cohort Studies

KW - Datasets as Topic

KW - Female

KW - Follow-Up Studies

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Heterozygote

KW - Humans

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide

KW - Risk Assessment/methods

KW - Risk Factors

UR - https://www.scopus.com/pages/publications/85107895788

U2 - 10.1038/s41467-021-22491-8

DO - 10.1038/s41467-021-22491-8

M3 - Journal article

C2 - 34099642

SN - 2041-1722

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3417

ER -

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

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Keywords

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