Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease

Objectives: Recent advances in high-resolution metabolomics platforms allow the simultaneous measurement of thousands of small molecules produced from metabolism (metabolites), providing a map of disease-related perturbations across interconnected pathways. We used high performance, untargeted metabolomics to identify metabolic disturbances and molecular events associated with Parkinson's disease (PD) in two population-based studies. Methods: We performed a metabolome-wide association study (MWAS) on PD, using serum-based untargeted metabolomics data derived from high resolution liquid chromatography, mass spectrometry (LCMS). We used two independent, case-control populations for discovery and replication (n=642 PD patients, n=277 controls). Results: From the LCMS, 5,145 metabolites were detected across the two study populations in [≥]50% of the samples (HILIC: 2913 metabolites; C18: 2063 metabolites). Using logistic regression and an FDR to correct for multiple testing, we determined 236 metabolites were associated with PD in a meta-analysis at an FDR<0.05. Of these, 110 metabolites were independently associated with PD in both discovery and replication studies at p<0.05 (187 at p<0.10), while 24 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, the microbial related metabolite, p-cresol (meta-OR=1.29, 95% CI=1.13, 1.47, FDR=0.01), and it's two metabolites, p-cresol sulfate and p-cresol glucuronide, were found at higher intensity among the PD patients relative to controls. P-cresol glucuronide was also associated with motor symptoms among patients. Pyroglutamic acid (meta OR=3.79, 95% CI=2.60, 5.54; FDR=5.30E-09), the anti-inflammatory metabolite itaconate (meta OR=0.47, 95% CI=0.36, 0.61; FDR=8.44E-06), and cysteine-S-sulfate (meta OR=1.56, 95% CI=1.32, 1.83; FDR=1.66E-05) were also among the most strongly associated metabolites. Seventeen pathways were also enriched, including several related to amino acid and lipid metabolism. Conclusions: Our results revealed PD-associated metabolites in two independent study populations, implicating individual metabolites including p-cresol and itaconate, as well as suggesting metabolic disturbances in amino acid and lipid metabolism and inflammatory processes.