Liu Chien-Cheng
Department of Anesthesiology, E-Da Hospital, I-Shou University, Kaohsiung City 82445, Taiwan.
School of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan.
Int J Mol Sci. 2025 Sep 6;26(17):8690. doi: 10.3390/ijms26178690.
The causal contributions of specific mitochondrial genes to common pain phenotypes remain unclear. We employed a multi-omics Mendelian randomization (SMR) approach, integrating QTL data (expression, methylation, protein) for mitochondrial genes with GWAS summary statistics for seven pain phenotypes. We identified 18 candidate genes with robust SMR associations across omics layers. However, strong colocalization evidence (PP.H4 > 0.7) was largely absent, pointing towards complex genetic architectures. A notable exception was a strong signal for a shared causal variant found at the methylation level for the MCL1 gene in hip pain (PP.H4 = 0.962), nominating it as a high-confidence candidate. Additionally, genetically predicted higher protein levels of Glycine amidinotransferase (GATM) showed consistent protective associations with neck or shoulder, back, and knee pain. This study provides novel evidence for mitochondrial gene regulation in pain, highlighting the GATM pathway as protective and identifying MCL1 methylation as a potential causal mechanism in hip pain.
特定线粒体基因对常见疼痛表型的因果贡献仍不清楚。我们采用了多组学孟德尔随机化（SMR）方法，将线粒体基因的QTL数据（表达、甲基化、蛋白质）与七种疼痛表型的GWAS汇总统计数据相结合。我们在各层组学中鉴定出18个具有稳健SMR关联的候选基因。然而，在很大程度上缺乏强共定位证据（PP.H4>0.7），这表明存在复杂的遗传结构。一个显著的例外是在髋部疼痛中发现MCL1基因甲基化水平存在共享因果变异的强信号（PP.H4 = 0.962），将其列为高可信度候选基因。此外，遗传预测的甘氨酸脒基转移酶（GATM）较高蛋白质水平显示出与颈部或肩部、背部和膝盖疼痛一致的保护关联。本研究为疼痛中的线粒体基因调控提供了新证据，突出了GATM途径的保护作用，并确定MCL1甲基化是髋部疼痛的潜在因果机制。
