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.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R01NS118146, R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG057777, NS097437, NS075321, NS097799 and NS07532), the Alzheimer Association (NIRG-11-200110, BAND-14-338165, AARG-16-441560, and BFG-15-362540), the American Parkinson Disease Association (APDA), the Greater St. Louis Chapter of the APDA, the Jo Riney Fund, the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), and the Paula and Roger Riney Fund. OH is an Archer Foundation Research Scientist. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
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.
AB - 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.
KW - APOE
KW - Alpha-synuclein
KW - Amyloid beta
KW - GWAS
KW - Parkinson disease
UR - http://www.scopus.com/inward/record.url?scp=85096293765&partnerID=8YFLogxK
U2 - 10.1186/s40478-020-01072-8
DO - 10.1186/s40478-020-01072-8
M3 - Article
C2 - 33213513
AN - SCOPUS:85096293765
SN - 2051-5960
VL - 8
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
M1 - 196
ER -