Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. Identify metabolic disturbances associated with Parkinson’s disease (PD) in two population-based studies using untargeted metabolomics. We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation. LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism. Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.

中文翻译：

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非靶向血清代谢组学揭示了帕金森病中氨基酸和脂质代谢的新代谢关联和破坏


非靶向高分辨率代谢组学分析可同时测量数千种代谢物。基于这些数据的代谢网络可以帮助发现相互关联的途径中与疾病相关的扰动。使用非靶向代谢组学在两项基于人群的研究中识别与帕金森病 (PD) 相关的代谢紊乱。我们使用基于血清的非靶向代谢组学数据进行了帕金森病的全代谢组关联研究 (MWAS)，这些数据源自液相色谱与高分辨率质谱 (LC-HRMS)，使用两个不同的基于人群的病例对照人群。我们还将我们的结果与之前发表的大规模非靶向 MWAS 中与 PD 相关的 34 种代谢物结合起来，以评估外部验证。 LC-HRMS 检测到 4,762 种代谢物进行分析（HILIC：2716 种代谢物；C18：2046 种代谢物）。我们确定了 296 个与 FDR<0.05 时的 PD 相关的特征，其中 134 个特征的 log2 倍数变化 (FC) 超过 ±0.5（228 个特征超过 ±0.25）。其中，104 例在发现和复制研究中与 PD 独立相关，p<0.05（170 例 p<0.10），而 27 例与 PD 患者中的左旋多巴等效剂量相关。有趣的是，外部验证的特征包括微生物相关代谢物、对甲酚葡萄糖苷酸（FC=2.52，95% CI=1.67、3.81，FDR=7.8e-04）和对甲酚硫酸盐。对甲酚葡萄糖苷酸也与患者的运动症状相关。其他经外部验证的与 PD 相关的代谢物包括苯乙酰基-L-谷氨酰胺、葫芦巴碱、犬尿氨酸、胆绿素和泛酸。新的关联包括抗炎代谢物衣康酸（FC=0.79，95% CI=0.73, 0.86；FDR=2.17E-06）和半胱氨酸-S-硫酸盐（FC=1.56，95% CI=1.39, 1.75；FDR= 3.43E-11）。 富集了十七条途径，其中包括一些与氨基酸和脂质代谢相关的途径。我们的结果揭示了与帕金森病相关的代谢物，证实了之前的一些观察结果，包括对甲酚葡萄糖醛酸，以及新发现的有趣的代谢物，例如衣康酸。我们的数据还表明帕金森病中氨基酸和脂质代谢以及炎症过程的代谢紊乱。