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• W3039506797 abstract "Abstract Alpha-Synuclein (α-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of α-Syn are not currently used as a clinical biomarker but may be a proxy for pathological α-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF α-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF α-Syn levels remain unknown. CSF levels of amyloid beta 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau 181 ) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control cohorts (combined N=1,960). CSF biomarker (α-Syn, Aβ42, t-tau, and p-tau 181 ) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE ε4, was associated with CSF Aβ42 levels (effect=-0.5, p=9.2×10 −19 ). Several genome-wide suggestive loci associated with CSF α-Syn, t-tau, or p-tau 181 were found. Polygenic risk scores (PRS) were constructed using the latest PD risk meta-analysis (49,731 PD cases and 784,343 controls) and the largest CSF biomarkers GWAS (N=3,146). PRS calculated using META-PD were associated with PD status in the four cohorts included in the present study (p= 2.2×10 −16 ). A highly significant correlation (Nagelkerke pseudo-R 2 =2.29%; p=2.5×10 −11 ) of the genomic architecture between CSF Aβ42 and PD risk was also found. Higher PRS scores were associated with lower CSF Aβ42 levels (p=7.3×10 −04 ). Two-sample Mendelian Randomization (MR) approach revealed that CSF Aβ42 plays a role in PD risk (p=1.4×10 −05 ) and age at onset (p=7.6×10 −06 ), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE ε4 allele was associated with significantly lower levels of CSF Aβ42 (p=3.8×10 −06 ), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8×10 −08 ) and higher Braak Aβ score (p=4.4×10 −04 ) in PD participants. Together these results from high-throughput and hypothesis-free approaches (GWAS, PRS and MR) converge on a genetic link between PD with CSF Aβ42 and APOE ." @default.
• W3039506797 created "2020-07-10" @default.
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• W3039506797 date "2020-07-03" @default.
• W3039506797 modified "2023-09-26" @default.
• W3039506797 title "Genome-wide association, Mendelian Randomization and polygenic risk score studies converge on a role of β−amyloid and APOE locus in Parkinson disease" @default.
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