Department of Neurology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
J Transl Med. 2022 Sep 30;20(1):437. doi: 10.1186/s12967-022-03648-5.
Metabolic disturbance has been reported in patients with epilepsy. Still, the evidence about the causal role of metabolites in facilitating or preventing epilepsy is lacking. Systematically investigating the causality between blood metabolites and epilepsy would help provide novel targets for epilepsy screening and prevention.
We conducted two-sample Mendelian randomization (MR) analysis. Data for 486 human blood metabolites came from a genome-wide association study (GWAS) comprising 7824 participants. GWAS data for epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium for primary analysis and the FinnGen consortium for replication and meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy.
482 out of 486 metabolites were included for MR analysis following rigorous genetic variants selection. After IVW and sensitivity analysis filtration, six metabolites with causal effects on epilepsy were identified from the ILAE consortium. Only four metabolites remained significant associations with epilepsy when combined with the FinnGen consortium [uridine: odds ratio (OR) = 2.34, 95% confidence interval (CI) = 1.48-3.71, P = 0.0003; 2-hydroxystearate: OR = 1.61, 95% CI = 1.19-2.18, P = 0.002; decanoylcarnitine: OR = 0.82, 95% CI = 0.72-0.94, P = 0.004; myo-inositol: OR = 0.77, 95% CI = 0.62-0.96, P = 0.02].
The evidence that the four metabolites mentioned above are associated with epilepsy in a causal way provides a novel insight into the underlying mechanisms of epilepsy by integrating genomics with metabolism, and has an implication for epilepsy screening and prevention.
已有报道称癫痫患者存在代谢紊乱，但代谢物在促进或预防癫痫发作中的因果作用证据仍不足。系统地研究血液代谢物与癫痫之间的因果关系有助于为癫痫筛查和预防提供新的靶点。
我们进行了两样本孟德尔随机化（MR）分析。来自包含 7824 名参与者的全基因组关联研究（GWAS）的数据包含 486 个人类血液代谢物。癫痫的 GWAS 数据来自国际抗癫痫联盟（ILAE）协会进行初步分析，芬兰遗传（FinnGen）协会进行复制和荟萃分析。进行敏感性分析以评估异质性和多效性。
在严格的遗传变异选择后，有 482 个代谢物纳入 MR 分析。经过 IVW 和敏感性分析过滤后，从 ILAE 协会确定了 6 个代谢物与癫痫有因果关系。当与 FinnGen 协会结合时，只有 4 个代谢物与癫痫仍存在显著关联[尿嘧啶：比值比（OR）=2.34，95%置信区间（CI）=1.48-3.71，P=0.0003；2-羟基硬脂酸：OR=1.61，95%CI=1.19-2.18，P=0.002；癸酰肉碱：OR=0.82，95%CI=0.72-0.94，P=0.004；肌醇：OR=0.77，95%CI=0.62-0.96，P=0.02]。
上述 4 种代谢物与癫痫呈因果关系的证据通过整合基因组学和代谢组学为癫痫的潜在机制提供了新的见解，并为癫痫筛查和预防提供了启示。
