Causal role of mitochondrial-related genes in autism spectrum disorder

doi:10.11852/zgetbjzz2024-1255

Abstract

Abstract: Objective To investigate the potential genetic mechanisms of mitochondrial-related genes in Autism Spectrum Disorder (ASD) using Summary-data-based Mendelian Randomization (SMR) and colocalization analysis based on multi-omics data. Methods Methylation quantitative trait loci (mQTLs), expression quantitative trait loci (eQTLs), and protein abundance quantitative trait loci (pQTLs) data were obtained from relevant QTL studies.The associations between mitochondrial-related genes and ASD were evaluated using SMR and colocalization analysis, and validated using datasets from FinnGen, UK Biobank (UKB), and the GWAS Catalog.The causal relationships between methylation, gene expression, and disease risk were further explored using SMR LocusPlot and SMR EffectPlot. Results The expression level of CHCHD3 was negatively associated with ASD risk (OR=0.27, 95%CI: 0.08-0.84).Lower methylation levels of NDUFA13 were associated with increased ASD risk, and upregulation of NDUFA13 expression increased ASD risk (OR=2.55, 95%CI: 1.03-6.28).Colocalization analysis further confirmed strong evidence for colocalization between the CHCHD3 methylation site (cg19918623) and multiple NDUFA13 methylation sites (cg03233793, cg07624705, cg25274157) with ASD risk (PP.H4 > 0.5). Conclusion Multi-omics evidence supports the potential association of mitochondrial-related genes CHCHD3 and NDUFA13 with ASD risk, providing new insights into the pathogenesis of ASD.

Key words: autism spectrum disorder, Mendelian randomization, mitochondrion, genetics, multi-omics level

摘要： 目的采用基于多组学数据的孟德尔随机化(SMR)和共定位分析,探讨线粒体相关基因在ASD中的潜在遗传机制。方法本研究从相关的QTL研究中获取甲基化(mQTLs)、基因表达(eQTLs)和蛋白质丰度(pQTLs)数据,结合SMR和共定位分析评估线粒体相关基因与ASD的关联,并使用FinnGen、UK Biobank(UKB)和GWAS Catalog数据集进行验证;通过SMR LocusPlot和SMR EffectPlot进一步探讨甲基化、基因表达与疾病风险之间的因果关系。结果 CHCHD3表达水平与ASD风险呈负相关(OR=0.27,95%CI:0.08~0.84),NDUFA13较低甲基化水平与ASD风险增加相关,通过上调NDUFA13表达增加ASD风险(OR=2.55,95%CI:1.03~6.28);共定位分析进一步确认,CHCHD3甲基化位点(cg19918623)和NDUFA13多个甲基化位点(cg03233793、cg07624705、cg25274157)与ASD风险具有较强共定位证据支持(PP.H4>0.5)。结论多组学证据支持线粒体相关基因CHCHD3和NDUFA13可能与ASD风险相关,为理解ASD的发病机制提供了新视角。

关键词: 孤独症谱系障碍, 孟德尔随机化, 线粒体, 遗传, 多组学水平

CLC Number:

R749.94

WANG Jian, LIU Chang, LIN lin, NIU Tingting, ZHANG Jianying. Causal role of mitochondrial-related genes in autism spectrum disorder[J]. Chinese Journal of Child Health Care, 2025, 33(11): 1212-1217.

王健, 刘畅, 林琳, 牛婷婷, 张建营. 线粒体相关基因在儿童孤独症谱系障碍中的因果作用探究[J]. 中国儿童保健杂志, 2025, 33(11): 1212-1217.

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