Objective: To use genome-wide association studies (GWASs) to identify genetic correlations between Parkinson’s disease (PD) and circulating metabolites.

Background: Metabolomics is the study of small molecules, or organic compounds with low molecular weight, in a biological system. In PD, there have been a number of small studies identifying metabolic differences in PD patients compared to controls, however findings have been inconsistent and lack replication. Here, we used Linkage Disequilibrium Score Regression (LDSC) to identify global genetic correlations between PD and metabolic traits. This method uses GWAS summary statistics and considers all SNP effects, including those below genome-wide significance. The aim of this study is to identify metabolites that may be important in PD as biomarkers or in disease pathogenesis. Although the gold standard will be large-scale metabolic profiling studies of PD patients, this approach could highlight metabolites which are important in PD.

Method: We used LDSC to identify genetic correlations between PD and 233 circulating metabolites. We used the PD GWAS summary statistics from the largest European ancestry PD GWAS by Nalls et al. [1]. For the metabolites, we used the summary statistics for 233 circulating metabolites from Karjalainen et al. [2]. Variants with a minor allele frequency < 1% were excluded. As many of the metabolites are correlated and not independent, we corrected for multiple testing according to the 28 independent factors which explained most of the variance in the metabolites, reported by Karjalainen et al. [2] (p < 0.0018).

Results: We identified only one significant genetic correlation between PD and metabolites which passed correction for multiple testing. This was for the ratio of cholesterol esters to total lipids in large low-density lipoproteins (LDL) (r = -0.16, p = 0.0006). There was also a nominally significant correlation between PD and the ratio of total cholesterol to total lipids in large LDL (r=-0.13, p = 0.006). No other correlations passed correction for multiple testing.

Conclusion: Our analyses suggest there is genetic overlap between PD and the ratio of cholesterol esters to total lipids in large LDL. This genetic correlation can help to provide insights into the aetiology of PD and prioritise causal relationships. We plan to conduct these analyses again with recently released summary statistics from new metabolites and PD GWASs.

References: [1] Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).
[2] Karjalainen, M. K. et al. Genome-wide characterization of circulating metabolic biomarkers. Nature 628, 130–138 (2024).

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-correlations-between-parkinsons-disease-and-circulating-metabolites/