Genome-wide association, Mendelian Randomization and polygenic risk score studies converge on a role of β−amyloid and APOE locus in Parkinson disease

Abstract

<jats:p>Alpha-Synuclein (a-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson's disease (PD). Cerebrospinal fluid (CSF) levels of a-Syn are not currently used as a clinical biomarker but may be a proxy for pathological a-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF a-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF a-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Ab42), total tau (t-tau), and phosphorylated tau181 (p-tau181) 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 (a-Syn, Ab42, t-tau, and p-tau181) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE e4, was associated with CSF Ab42 levels (effect=-0.5, p=9.2x10-19). Several genome-wide suggestive loci associated with CSF a-Syn, t-tau, or p-tau181 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= 2.2x10-16). A highly significant correlation (Nagelkerke pseudo-R2 =2.29%; p=2.5x10-11) of the genomic architecture between CSF Ab42 and PD risk was also found. Higher PRS scores were associated with lower CSF Ab42 levels (p=7.3x10-04). Two-sample Mendelian Randomization (MR) approach revealed that CSF Ab42 plays a role in PD risk (p=1.4x10-05) and age at onset (p=7.6x10-06), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE e4 allele was associated with significantly lower levels of CSF Ab42 (p=3.8x10-06), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8x10-08) and higher Braak Ab; score (p=4.4x10-04) 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 Ab42 and APOE.</jats:p>