Abstract
Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
Original language | English |
---|---|
Pages (from-to) | 1663-1674 |
Number of pages | 12 |
Journal | Alzheimer's and Dementia |
Volume | 17 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2021 |
Externally published | Yes |
Keywords
- APOE
- APP
- Alzheimer's disease
- BACE1
- PSEN2
- endophenotype
- genetic epidemiology
- genome‑wide association study
- plasma amyloid beta levels
- plasma biomarkers
- preclinical biomarkers
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In: Alzheimer's and Dementia, Vol. 17, No. 10, 10.2021, p. 1663-1674.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2
T2 - A genome-wide association study in over 12,000 non-demented participants
AU - Alzheimer's Disease Neuroimaging Initiative
AU - Damotte, Vincent
AU - van der Lee, Sven J.
AU - Chouraki, Vincent
AU - Grenier-Boley, Benjamin
AU - Simino, Jeannette
AU - Adams, Hieab
AU - Tosto, Giuseppe
AU - White, Charles
AU - Terzikhan, Natalie
AU - Cruchaga, Carlos
AU - Knol, Maria J.
AU - Li, Shuo
AU - Schraen, Susanna
AU - Grove, Megan L.
AU - Satizabal, Claudia
AU - Amin, Najaf
AU - Berr, Claudine
AU - Younkin, Steven
AU - Gottesman, Rebecca F.
AU - Buée, Luc
AU - Beiser, Alexa
AU - Knopman, David S.
AU - Uitterlinden, Andre
AU - DeCarli, Charles
AU - Bressler, Jan
AU - DeStefano, Anita
AU - Dartigues, Jean François
AU - Yang, Qiong
AU - Boerwinkle, Eric
AU - Tzourio, Christophe
AU - Fornage, Myriam
AU - Ikram, M. Arfan
AU - Amouyel, Philippe
AU - de Jager, Phil
AU - Reitz, Christiane
AU - Mosley, Thomas H.
AU - Lambert, Jean Charles
AU - Seshadri, Sudha
AU - van Duijn, Cornelia M.
N1 - Funding Information: : This research was made possible by financial support from the Netherlands Organization for Scientific Research and the Health Research Development Council. Epidemiological Prevention Study of Zoetermeer Funding Information: : This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contracts N01‐HC‐25195 and HHSN268201500001I). This study was also supported by grants from the National Institute on Aging: AG054076, U01‐AG049505, and AG008122 (S. Seshadri). S. Seshadri, A. Beiser, and Q. Yang were also supported by additional grants from the National Institute on Aging (R01AG049607, AG033193, AG033040) and the National Institute of Neurological Disorders and Stroke (R01‐NS017950, R01‐NS087541). The SHARe (SNP Health Association Resource) project was funded by the National Heart, Lung, and Blood Institute. The Linux Cluster for Genetic Analysis (LinGA‐II) on which part of the FHS computations were performed, was funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Framingham Heart Study Funding Information: : Data collection and sharing for this project was supported by the Washington Heights‐Inwood Columbia Aging Project (WHICAP, PO1AG007232, R01AG037212, RF1AG054023) funded by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. This work was also supported by National Institutes of Health grants AG042483, AG034189, and AG045334. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. We acknowledge the WHICAP study participants and the WHICAP research and support staff for their contributions to this study. The Columbia University Institutional Review Board reviewed and approved this project. All individuals provided written informed consent. Washington Heights‐Inwood Community Aging Project Funding Information: : The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of the Illumina exome chip v1.0 array data for the Rotterdam Study (RS‐I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine ( www.glimdna.org ), Erasmus MC, Rotterdam, The Netherlands. The generation and management of GWAS genotype data for the Rotterdam Study (RS‐I, RS‐II, RS‐III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911‐03‐012); the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; the Research Institute for Diseases in the Elderly (014‐93‐015; RIDE2); the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050‐060‐810. Carolina Medina‐Gomez, Lennard Karsten, and Linda Broer, for QC and variant calling; Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters, and Carolina Medina‐Gomez, for their help in creating the GWAS database. The work for this manuscript was further supported by ADAPTED: Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development (number 115975); the CoSTREAM project ( www.costream.eu ) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Rotterdam Study Funding Information: : Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Alzheimer's Disease Neuroimaging Initiative Funding Information: : The Erasmus Rucphen Family (ERF) has received funding from the Centre for Medical Systems Biology (CMSB) and Netherlands Consortium for Systems Biology (NCSB), both within the framework of the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). ERF study is also a part of EUROSPAN (European Special Populations Research Network; FP6 STRP grant number 018947 [LSHG‐CT‐2006‐01947]); European Network of Genomic and Genetic Epidemiology (ENGAGE) from the European Community's Seventh Framework Programme (FP7/2007‐2013)/grant agreement HEALTH‐F4‐2007‐201413; “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2‐CT‐2002‐01254); FP7 project EUROHEADPAIN (nr 602633), the Internationale Stichting Alzheimer Onderzoek (ISAO); the Hersenstichting Nederland (HSN); and the JNPD under the project PERADES (grant number 733051021, Defining Genetic, Polygenic and Environmental Risk for Alzheimer's Disease using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics). This work in the ERF study was conducted under the grants: ADAPTED: Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development (number 115975); the CoSTREAM project ( www.costream.eu ); and has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, and P. Snijders for his help in data collection. Eramus Rucphen Family Study Funding Information: : This work was supported by INSERM, the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease) including funding from MEL (Metropoleeuropéenne de Lille), ERDF (European Regional Development Fund), Conseil Régional Nord Pas de Calais, and the JPND‐funded PERADES project. The Three City Study was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi‐Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. The Three City biological bank was developed and maintained by the laboratory for genomic analysis LAG‐BRC ‐ Institut Pasteur de Lille. The work for this manuscript was further supported by the CoSTREAM project ( www.costream.eu ) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Three City Study Funding Information: The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institute of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/08/20. Funding Information: : The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Neurocognitive data was collected by U01 HL096812, HL096814, HL096899, HL096902, and HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), with previous brain MRI examinations funded by R01HL70825 from the NHLBI. Infrastructure was partially supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The authors thank the staff and participants of the ARIC study for their important contributions. Atherosclerosis Risk in Communities Study Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association
PY - 2021/10
Y1 - 2021/10
N2 - Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
AB - Introduction: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD.
KW - APOE
KW - APP
KW - Alzheimer's disease
KW - BACE1
KW - PSEN2
KW - endophenotype
KW - genetic epidemiology
KW - genome‑wide association study
KW - plasma amyloid beta levels
KW - plasma biomarkers
KW - preclinical biomarkers
UR - http://www.scopus.com/inward/record.url?scp=85113358825&partnerID=8YFLogxK
U2 - 10.1002/alz.12333
DO - 10.1002/alz.12333
M3 - Article
AN - SCOPUS:85113358825
SN - 1552-5260
VL - 17
SP - 1663
EP - 1674
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 10
ER -