Title | Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Ibañez L, Bahena JA, Yang C, Dube U, Farias FHG, Budde JP, Bergmann K, Brenner-Webster C, Morris JC, Perrin RJ, Cairns NJ, O'Donnell J, Alvarez I, Diez-Fairen M, Aguilar M, Miller R, Davis AA, Pastor P, Kotzbauer P, Campbell MC, Perlmutter JS, Rhinn H, Harari O, Cruchaga C, Benitez BA |
Journal | Acta Neuropathol Commun |
Volume | 8 |
Issue | 1 |
Pagination | 196 |
Date Published | 2020 11 19 |
ISSN | 2051-5960 |
Keywords | Aged, Aged, 80 and over, alpha-Synuclein, Amyloid beta-Peptides, Apolipoprotein E4, Apolipoproteins E, Brain, Female, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Parkinson Disease, Peptide Fragments, Phosphorylation, tau Proteins |
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 beta, total tau, and phosphorylated tau 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 beta levels (effect = - 0.5, p = 9.2 × 10). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau 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 beta (R = 2.29%; p = 2.5 × 10). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta levels (p = 7.3 × 10). Two-sample Mendelian Randomization revealed that CSF amyloid beta plays a role in Parkinson's disease (p = 1.4 × 10) and age at onset (p = 7.6 × 10), 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 beta (p = 3.8 × 10), higher mean cortical binding potentials (p = 5.8 × 10), and higher Braak amyloid beta score (p = 4.4 × 10). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta, and APOE. |
DOI | 10.1186/s40478-020-01072-8 |
Pubmed Link | https://www.ncbi.nlm.nih.gov/pubmed/33213513?dopt=Abstract |
page_expo | External |
Alternate Journal | Acta Neuropathol Commun |
PubMed ID | 33213513 |
PubMed Central ID | PMC7678051 |
Grant List | P30 AG066444 / AG / NIA NIH HHS / United States RF1 AG053303 / AG / NIA NIH HHS / United States K08 NS101118 / NS / NINDS NIH HHS / United States P01 AG026276 / AG / NIA NIH HHS / United States R01 NS097437 / NS / NINDS NIH HHS / United States R01 NS097799 / NS / NINDS NIH HHS / United States RF1 AG044546 / AG / NIA NIH HHS / United States R01 NS118146 / NS / NINDS NIH HHS / United States R01NS097799 / NS / NINDS NIH HHS / United States NS075321 / NS / NINDS NIH HHS / United States R01AG057777 / AG / NIA NIH HHS / United States R01 AG057777 / AG / NIA NIH HHS / United States U01 AG058922 / AG / NIA NIH HHS / United States R01 AG044546 / AG / NIA NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States |
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