Objective: To identify common genetic variants associated with biological measures that have been implicated in Parkinson’s disease and related synucleinopathies.

Background: Alpha synucleinopathies, mainly including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders that present with varied symptoms and clinical overlap that make accurate diagnosis a challenge. Biomarkers can be a measurable indicator of disease onset and progression, and could increase diagnostic accuracy. However, genetic factors can influence biomarker levels in unforeseen ways, impacting their usability and potentially biasing research outcomes. Understanding these genetic modulators can help inform clinical trials by improving participant selection.

Method: We attempted to uncover all common genetic variation that was associated with each biomarker with data in over 450 PD patients, controls, and prodromal individuals in the Parkinson’s Progression Markers Initiative (PPMI) cohort using genome-wide association studies (GWAS). GWASs were conducted on 76 biological measures with adjustments for age, sex, disease status, and the top 5 PCs.

Results: We observed notable results for multiple GWASs. The APOE e4 allele was associated with decreased amyloid beta in CSF (rs429358, beta = -208.5, se = 29.2, p = 9.7e-13). Urine BMP isoforms were positively associated with LRRK2 p.G2019S and negatively associated with GBA1 p.N370S. The GBA1 association remained significant after adjusting for p.G2019S status. Mendelian randomization found potentially causative effects for multiple BMP isoforms on PD status (total di-22:6-BMP, IVW, p = 0.049, se = 0.07, beta = 0.1; 2,2’-di-22:6-BMP, IVW, p = 0.018, se = 0.07, beta = 0.1). An intergenic locus near TP63 was negatively associated with CSF t-tau (rs1424826, beta = -0.09, se = 0.02, p = 9.2e-09) and was just shy of significant for phosphorylated p-tau (beta = -0.08, se = 0.02, p = 7.2e-08). Multiple isoforms of CSF ceramide were associated with the MCF2L2 locus (3:183225125:C:T, beta = -0.5, se = 0.09, p = 2.2e-08) and an intergenic locus near ARMH2 (rs2817735, beta = 0.5, se = 0.08, p = 2.7e-09).

Conclusion: Our findings identify previously supported associations while also identifying novel ones. These genetic loci can be taken into account to properly utilize these biological measures as biomarkers in future synucleinopathy and neurodegenerative disease research.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/common-genetic-variation-associated-with-parkinsons-disease-biological-measures/