TY - JOUR
T1 - Genetic overlap between Alzheimer's disease and blood lipid levels
AU - van der Linden, Robert J.
AU - Reus, Lianne M.
AU - de Witte, Ward
AU - Tijms, Betty M.
AU - Olde Rikkert, Marcel
AU - Visser, Pieter Jelle
AU - Poelmans, Geert
N1 - Funding Information: The research presented in this paper was supported by the Dutch charity foundation 'Stichting Devon'. In addition, research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. Analyses were supported by the EU-PRISM Project ( www.prism-project.eu ), which received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916 . This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. PJV also received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking for the EMIF Project (grant agreement No 115372 ). Funding sources had no role in design and conduct of the study, data collection, data analysis, data interpretation, or in writing or approval of this report. Furthermore, we want to acknowledge the participants and investigators of the FinnGen study. Publisher Copyright: © 2021 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - Late-onset Alzheimer's disease (AD) has a significant genetic component, but the molecular mechanisms through which genetic risk factors contribute to AD pathogenesis are unclear. We screened for genetic sharing between AD and the blood levels of 615 metabolites to elucidate how the polygenic architecture of AD affects metabolomic profiles. We retrieved summary statistics from genome-wide association studies of AD and the metabolite blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 31 metabolites, all of which were lipids, we identified and replicated genetic sharing with AD. We also found a positive genetic concordance - implying that genetic risk factors for AD are associated with higher blood levels - for 16 of the 31 replicated metabolites. In the brain, lipids and their intermediate metabolites have essential structural and functional roles, such as forming and dynamically regulating synaptic membranes. Our results imply that genetic risk factors for AD affect lipid levels, which may be leveraged to develop novel treatment strategies for AD.
AB - Late-onset Alzheimer's disease (AD) has a significant genetic component, but the molecular mechanisms through which genetic risk factors contribute to AD pathogenesis are unclear. We screened for genetic sharing between AD and the blood levels of 615 metabolites to elucidate how the polygenic architecture of AD affects metabolomic profiles. We retrieved summary statistics from genome-wide association studies of AD and the metabolite blood levels and assessed for shared genetic etiology, using a polygenic risk score-based approach. For the blood levels of 31 metabolites, all of which were lipids, we identified and replicated genetic sharing with AD. We also found a positive genetic concordance - implying that genetic risk factors for AD are associated with higher blood levels - for 16 of the 31 replicated metabolites. In the brain, lipids and their intermediate metabolites have essential structural and functional roles, such as forming and dynamically regulating synaptic membranes. Our results imply that genetic risk factors for AD affect lipid levels, which may be leveraged to develop novel treatment strategies for AD.
KW - Alzheimer's disease
KW - Human genetics
KW - Lipoproteins
KW - Metabolomics: Brain
KW - Polygenic Risk Scores (PRS)
UR - http://www.scopus.com/inward/record.url?scp=85111569270&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.neurobiolaging.2021.06.019
DO - https://doi.org/10.1016/j.neurobiolaging.2021.06.019
M3 - Article
C2 - 34340865
SN - 0197-4580
VL - 108
SP - 189
EP - 195
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -