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Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease.
Acta Neuropathol Commun. 2020 11 19; 8(1):196.AN

Abstract

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1-42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1-42 levels (effect = - 0.5, p = 9.2 × 10-19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1-42 (R2 = 2.29%; p = 2.5 × 10-11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1-42 levels (p = 7.3 × 10-04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1-42 plays a role in Parkinson's disease (p = 1.4 × 10-05) and age at onset (p = 7.6 × 10-06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1-42 (p = 3.8 × 10-06), higher mean cortical binding potentials (p = 5.8 × 10-08), and higher Braak amyloid beta score (p = 4.4 × 10-04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta1-42, and APOE.

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Authors+Show Affiliations

Ibanez L
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Bahena JA
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Yang C
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Dube U
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Farias FHG
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Budde JP
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Bergmann K
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Brenner-Webster C
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA.
Morris JC
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Perrin RJ
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Department of Pathology and Immunology, Washington University, St. Louis, MO, 63110, USA.
Cairns NJ
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Department of Pathology and Immunology, Washington University, St. Louis, MO, 63110, USA. College of Medicine and Health, University of Exeter, Exeter, Devon, UK.
O'Donnell J
Department of Neurology, Washington University, St. Louis, MO, 63110, USA.
Álvarez I
Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain. Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
Diez-Fairen M
Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain. Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
Aguilar M
Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain. Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
Miller R
Department of Neurology, Washington University, St. Louis, MO, 63110, USA.
Davis AA
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA.
Pastor P
Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain. Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, University of Barcelona, Terrassa, Barcelona, Spain.
Kotzbauer P
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA.
Campbell MC
Department of Neurology, Washington University, St. Louis, MO, 63110, USA. Departments of Neuroscience and Radiology, Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, 63110, USA.
Perlmutter JS
Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. Department of Neurology, Washington University, St. Louis, MO, 63110, USA. Departments of Neuroscience and Radiology, Programs in Physical Therapy and Occupational Therapy, Washington University, St. Louis, MO, 63110, USA.
Rhinn H
Department of Bioinformatics, Alector, INC, San Francisco, CA, 94080, USA.
Harari O
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA. Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Cruchaga C
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA. Hope Center for Neurologic Disorders, Washington University, St. Louis, MO, 63110, USA. The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Benitez BA
Department of Psychiatry, BJC Institute of Health, Washington University School of Medicine, Box 8134, 425 S. Euclid Ave., St. Louis, MO, 63110, USA. babenitez@wustl.edu. NeuroGenomics and Informatics Center, Washington University, St. Louis, MO, 63110, USA. babenitez@wustl.edu.

MeSH

AgedAged, 80 and overAmyloid beta-PeptidesApolipoprotein E4Apolipoproteins EBrainFemaleGenome-Wide Association StudyHumansMaleMendelian Randomization AnalysisMiddle AgedParkinson DiseasePeptide FragmentsPhosphorylationalpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33213513

Citation

Ibanez, Laura, et al. "Functional Genomic Analyses Uncover APOE-mediated Regulation of Brain and Cerebrospinal Fluid Beta-amyloid Levels in Parkinson Disease." Acta Neuropathologica Communications, vol. 8, no. 1, 2020, p. 196.
Ibanez L, Bahena JA, Yang C, et al. Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. Acta Neuropathol Commun. 2020;8(1):196.
Ibanez, L., Bahena, J. A., Yang, C., Dube, U., Farias, F. H. G., Budde, J. P., Bergmann, K., Brenner-Webster, C., Morris, J. C., Perrin, R. J., Cairns, N. J., O'Donnell, J., Álvarez, I., Diez-Fairen, M., Aguilar, M., Miller, R., Davis, A. A., Pastor, P., Kotzbauer, P., ... Benitez, B. A. (2020). Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. Acta Neuropathologica Communications, 8(1), 196. https://doi.org/10.1186/s40478-020-01072-8
Ibanez L, et al. Functional Genomic Analyses Uncover APOE-mediated Regulation of Brain and Cerebrospinal Fluid Beta-amyloid Levels in Parkinson Disease. Acta Neuropathol Commun. 2020 11 19;8(1):196. PubMed PMID: 33213513.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. AU - Ibanez,Laura, AU - Bahena,Jorge A, AU - Yang,Chengran, AU - Dube,Umber, AU - Farias,Fabiana H G, AU - Budde,John P, AU - Bergmann,Kristy, AU - Brenner-Webster,Carol, AU - Morris,John C, AU - Perrin,Richard J, AU - Cairns,Nigel J, AU - O'Donnell,John, AU - Álvarez,Ignacio, AU - Diez-Fairen,Monica, AU - Aguilar,Miquel, AU - Miller,Rebecca, AU - Davis,Albert A, AU - Pastor,Pau, AU - Kotzbauer,Paul, AU - Campbell,Meghan C, AU - Perlmutter,Joel S, AU - Rhinn,Herve, AU - Harari,Oscar, AU - Cruchaga,Carlos, AU - Benitez,Bruno A, Y1 - 2020/11/19/ PY - 2020/11/02/received PY - 2020/11/03/accepted PY - 2020/11/20/entrez PY - 2020/11/21/pubmed PY - 2021/11/10/medline KW - APOE KW - Alpha-synuclein KW - Amyloid beta KW - GWAS KW - Parkinson disease SP - 196 EP - 196 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 8 IS - 1 N2 - Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1-42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1-42 levels (effect = - 0.5, p = 9.2 × 10-19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1-42 (R2 = 2.29%; p = 2.5 × 10-11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1-42 levels (p = 7.3 × 10-04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1-42 plays a role in Parkinson's disease (p = 1.4 × 10-05) and age at onset (p = 7.6 × 10-06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1-42 (p = 3.8 × 10-06), higher mean cortical binding potentials (p = 5.8 × 10-08), and higher Braak amyloid beta score (p = 4.4 × 10-04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta1-42, and APOE. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/33213513/Functional_genomic_analyses_uncover_APOE_mediated_regulation_of_brain_and_cerebrospinal_fluid_beta_amyloid_levels_in_Parkinson_disease_ DB - PRIME DP - Unbound Medicine ER -