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

doi:10.11852/zgetbjzz2024-1255

中国儿童保健杂志 ›› 2025, Vol. 33 ›› Issue (11): 1212-1217.DOI: 10.11852/zgetbjzz2024-1255

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

王健¹, 刘畅², 林琳³, 牛婷婷¹, 张建营¹

1.青岛大学附属山东省妇幼保健院,山东济南 250014;
2.菏泽医学专科学校;
3.威海市妇幼保健院

收稿日期:2024-10-21 修回日期:2025-03-01 发布日期:2025-11-11 出版日期:2025-11-10
通讯作者: 张建营,E-mail:kuzy3@126.com
作者简介:王健(1992—),男,主治医师,硕士学位,主要研究方向为儿童发育行为疾病。
基金资助:
山东省中医药科技面上项目(2020M051)

Causal role of mitochondrial-related genes in autism spectrum disorder

WANG Jian¹,LIU Chang²,LIN lin³,NIU Tingting¹,ZHANG Jianying¹

1. Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, Shandong 250014, China;
2. Heze Medical College;
3. Weihai Maternal and Child Health Hospital

Received:2024-10-21 Revised:2025-03-01 Online:2025-11-10 Published:2025-11-11
Contact: ZHANG Jianying, E-mail: kuzy3@126.com

摘要/Abstract

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

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

中图分类号:

R749.94

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.

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.

参考文献

[1] Bai D, Yip BHK, Windham GC, et al.Association ofgenetic and environmental factors with autism in a 5-country cohort[J].JAMA Psychiatry, 2019, 76(10):1035.
[2] Finsterer J.Autism spectrum disorder: A mitochondrial disorder[J].Iran J Child Neurol, 2021,15(4):115-117.
[3] Frye RE, Rincon N, McCarty PJ, et al.Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and Meta-analysis[J].Neurobiol Dis,2024,197:106520.
[4] Frye RE.Mitochondrial Dysfunction inautism spectrum disorder: Unique abnormalities and targeted treatments[J].Semin Pediatr Neurol, 2020,35:100829.
[5] Tang X, Feng C, Zhao Y, et al.A study of genetic heterogeneity in autism spectrum disorders based on plasma proteomic and metabolomic analysis: Multiomics study of autism heterogeneity[J].MedComm (2020),2023, 4(5):e380.
[6] Brister D, Rose S, Delhey L, et al.Metabolomicsignatures of autism spectrum disorder[J].J Pers Med, 2022,12(10):1727.
[7] Singh K, Singh IN, Diggins E, et al.Developmental regression and mitochondrial function in children with autism[J].Ann Clin Transl Neurol, 2020, 7(5):683-694.
[8] Yui K, Sato A, Imataka G.Mitochondrial dysfunction and its relationship with mTOR signaling and oxidative damage in autism spectrum disorders[J].Mini Rev Med Chem, 2015,15(5):373-389.
[9] Mehta R, Kuhad A, Bhandari R.Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders[J].Expert Opin Ther Targets, 2022, 26(7):659-679.
[10] Rojas-Charry L, Nardi L, Methner A, et al.Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders[J].J Mol Med (Berl),2021,99(2):161-178.
[11] Rath S, Sharma R, Gupta R, et al.MitoCarta3.0:An updated mitochondrial proteome now with sub-organelle localization and pathway annotations[J].Nucleic Acids Res,2021,49(D1):D1541-D1547.
[12] Wu Y, Zeng J, Zhang F, et al.Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits[J].Nat Commun, 2018, 9(1):918.
[13] Võsa U, Claringbould A, Westra HJ, et al.Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression[J].Nat Genet,2021, 53(9):1300-1310.
[14] Pietzner M, Wheeler E, Carrasco-Zanini J, et al.Mapping the proteo-genomic convergence of human diseases[J].Science,2021, 374(6569):eabj1541.
[15] Zhu Z, Zhang F, Hu H, et al.Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets[J].Nat Genet, 2016, 48(5):481-487.
[16] Vue Z, Neikirk K, Vang L, et al.Three-dimensional mitochondria reconstructions of murine cardiac muscle changes in size across aging[J].Am J Physiol Heart Circ Physiol, 2023, 325(5):H965-H982.
[17] Lionel AC, Crosbie J, Barbosa N, et al.Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD[J].Sci Transl Med,2011,3(95):95ra75.
[18] Darshi M, Mendiola VL, Mackey MR, et al.ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity and mitochondrial function[J].J Biol Chem, 2011, 286(4):2918-2932.
[19] Gevezova M, Sbirkov Y, Sarafian V, et al.Autistic spectrum disorder (ASD)-Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment[J].Brain Behav Immun Health,2023, 30:100646.
[20] Hu H, Nan J, Sun Y, et al.Electron leak from NDUFA13 within mitochondrial complex I attenuates ischemia-reperfusion injury via dimerized STAT3[J].Proc Natl Acad Sci U S A, 2017,114(45):11908-11913.
[21] Angebault C, Charif M, Guegen N, et al.Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability[J].Hum Mol Genet,2015,24(14):3948-3955.
[22] Liu X, Lin J, Zhang H, et al.Oxidativestress in autism spectrum disorder-current progress of mechanisms and biomarkers[J].Front Psychiatry,2022, 13:813304.
[23] Viana CE, Bortolotto VC, Araujo SM, et al.Lutein-loaded nanoparticles reverse oxidative stress, apoptosis, and autism spectrum disorder-like behaviors induced by prenatal valproic acid exposure in female rats[J].Neurotoxicology, 2023,94:223-234.

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

Causal role of mitochondrial-related genes in autism spectrum disorder

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

[1]	宋然然, 张娇. 基于认知、神经与遗传的汉语阅读障碍多维度机制研究[J]. 中国儿童保健杂志, 2025, 33(9): 939-943.
[2]	朱冰泉, 吕丽娜, 齐晔, 陈赛景, 刘丹. 孟德尔随机化法分析循环氨基酸与孤独症谱系障碍的因果关系研究[J]. 中国儿童保健杂志, 2025, 33(9): 954-958.
[3]	赵春娟, 卢伯华, 王贤, 刘晔, 崔丽茹. 全基因组测序技术在婴儿遗传性疾病筛查中的应用[J]. 中国儿童保健杂志, 2025, 33(9): 1035-1040.
[4]	许玥, 郜统勋, 胡思源, 李梅芳, 栾奕博, 许晨霞. ω-3/6多不饱和脂肪酸与儿童肥胖的两样本孟德尔随机化研究[J]. 中国儿童保健杂志, 2025, 33(8): 841-847.
[5]	王文, 王喆, 蒋秀蕾, 姜妍琳, 胡英华, 王明月, 牟春笋, 王春香. 基于孟德尔随机化探讨肠道菌群及代谢通路与矮身材的因果关系[J]. 中国儿童保健杂志, 2025, 33(8): 854-859.
[6]	汪瑜, 李妍, 朱绘霖, 曹伟, 邹小兵. 具有学者技能的孤独症谱系障碍儿童认知行为特征的初步研究[J]. 中国儿童保健杂志, 2025, 33(7): 702-706.
[7]	姜含笑, 乔艺, 屈艳琳. 肠道菌群与注意缺陷多动障碍和孤独症谱系障碍的孟德尔随机化分析[J]. 中国儿童保健杂志, 2025, 33(7): 707-714.
[8]	王飞英, 秦宏超, 陶小冬, 瞿秋婵, 倪勇, 许占斌. 孤独症谱系障碍儿童超重/肥胖现况及其与情绪行为问题的相关性[J]. 中国儿童保健杂志, 2025, 33(7): 729-732.
[9]	靳少举, 李艳, 徐胜. 孤独症谱系障碍儿童情绪失调的国外研究进展[J]. 中国儿童保健杂志, 2025, 33(7): 755-759.
[10]	凌梅, 汪月红, 李娜, 熊玉红, 杨舒, 徐桂凤. 孤独症谱系障碍微生物-肠-脑轴研究进展[J]. 中国儿童保健杂志, 2025, 33(7): 778-782.
[11]	李诺, 周园, 钱旭光, 刘振寰, 庞碧徽, 徐立宝, 姚向歌, 赵勇. 超低频经颅磁刺激治疗儿童孤独症谱系障碍合并睡眠障碍的临床研究[J]. 中国儿童保健杂志, 2025, 33(7): 790-795.
[12]	徐海萍, 丁丹丹, 朱义如, 杜晓艳, 黄丽洁, 张雪琴, 代晶晶. 基于行为转变理论的营养健康教育对孤独症谱系障碍儿童饮食行为干预效果研究[J]. 中国儿童保健杂志, 2025, 33(7): 807-812.
[13]	中国妇幼保健协会儿童自闭症防治专委会, 《中国儿童保健杂志》编委会. 孤独症谱系障碍防治三级网络规范化建设专家共识[J]. 中国儿童保健杂志, 2025, 33(6): 581-589.
[14]	张林, 张建平, 江才明, 邵智. 基于功能性近红外光谱的学龄前孤独症谱系障碍儿童脑功能特征研究[J]. 中国儿童保健杂志, 2025, 33(6): 597-602.
[15]	王玲, 吕莹, 李秋菊. 不同性别和年龄孤独症谱系障碍儿童发育水平及症状严重程度分析[J]. 中国儿童保健杂志, 2025, 33(6): 619-622.