目的 探讨儿童皮质下脑结构与孤独症谱系障碍(ASD)的因果关系,为ASD的早期诊断提供潜在的生物标志物。方法 从全基因组关联研究库(GWAS)的公开数据中提取与儿童皮质下脑结构和ASD相关的数据,采用两样本孟德尔随机化研究方法进行因果推断。主要采用逆方差加权法(IVW),并结合MR-Egger回归法、加权中位数法和加权众数法来消除IVW的局限性。以Cochran′s Q 检验、MR-PRESSO和留一法进行质量控制分析。结果 3种儿童皮质下脑结构表型与ASD存在因果关联,双侧尾状核体积与ASD呈正相关(IVW:OR=1.220,95%CI:1.088~1.369,P=0.001)、双侧伏隔核体积×产前应激的交互效应与ASD呈负相关(IVW:OR=0.850,95%CI:0.734~0.983,P=0.029)、双侧颅内体积×出生后应激的交互效应与ASD呈负相关(IVW:OR=0.878,95%CI:0.780~ 0.988,P=0.031)。敏感性分析提示结果稳定可靠。结论 儿童皮质下脑结构中,双侧尾状核体积是ASD发生的危险生物标志物,体积的增加可能标志着ASD发病风险;双侧伏隔核体积×产前应激的交互效应、双侧颅内体积×出生后应激的交互效应是ASD发生的保护因素,随着相应交互效应的增强可能降低ASD的发病风险。本研究可为ASD早期诊断提供参考。
Abstract
Objective To investigate the causal relationship between subcortical brain structures and autism spectrum disorder (ASD) in children, in order to identify potential biomarkers for early ASD diagnosis. Methods The data related to children′s subcortical brain structure and ASD were extracted from the open data of the genome-wide association study (GWAS), and the two-sample Mendelian randomization method was used for causal inference.The inverse-variance weighted (IVW) method served as the primary analysis, supplemented by MR-Egger regression, weighted median, and weighted mode methods to address IVW limitations.Quality control was conducted using Cochran′s Q test, MR-PRESSO, and leave-one-out analysis. Results Three subcortical structural phenotypes showed causal associations with ASD: 1) The bilateral caudate nucleus volume was positively correlated with ASD (IVW: OR=1.220, 95%CI: 1.088 - 1.369, P=0.001); 2) the interaction between bilateral nucleus accumbens volume and prenatal stress exhibited a negative association with ASD (IVW: OR=0.850, 95%CI:0.734 - 0.983,P=0.029); 3) bilateral intracranial volum×postnatal stress interaction was negatively correlated with ASD (IVW: OR=0.878, 95%CI:0.780 - 0.988, P=0.031).Sensitivity analyses confirmed robust findings. Conclusions Increased bilateral caudate nucleus volume may represent a risk biomarker for ASD, while the protective interaction effects of nucleus accumbens volume × prenatal stress and intracranial volume × postnatal stress could mitigate ASD risk.These findings may provide potential neuroanatomical markers for early ASD detection.
关键词
儿童皮质下脑结构 /
孤独症谱系障碍 /
孟德尔随机化
Key words
children′s subcortical brain structure /
autism spectrum disorder /
Mendelian randomization
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参考文献
[1] Lai MC, Lombardo MV, Baron-Cohen S.Autism[J].Lancet,2014,383(9920):896-910.
[2] Shaw KA, Williams S, Patrick ME, et al.Prevalence and early identification of autism spectrum disorder among children aged 4 and 8 years - autism and developmental disabilities monitoring network, 16 Sites, United States, 2022[J].MMWR Surveill Summ,2025,74(2):1-22.
[3] Zhou H, Xu X, Yan W, et al.Prevalence of autism spectrum disorder in China: A nationwide multi-center population-based study among children aged 6 to 12 years[J].Neurosci Bull,2020,36(9):961-971.
[4] Lord C, Elsabbagh M, Baird G, et al.Autism spectrum disorder[J].Lancet,2018,392(10146):508-520.
[5] Libero LE, Reid MA, White DM, et al.Biochemistry of the cingulate cortex in autism: An MR spectroscopy study[J].Autism Res.2016,9(6):643-657.
[6] Wang H, Ma ZH, Xu LZ, et al.Developmental brain structural atypicalities in autism: A voxel-based morphometry analysis[J].Child Adolesc Psychiatry Ment Health, 2022,16(1):7.
[7] Habata K, Cheong Y, Kamiya T, et al.Relationship between sensory characteristics and cortical thickness/volume in autism spectrum disorders[J].Transl Psychiatry,2021,11(1):616.
[8] Burgess S, Davey Smith G, Davies NM, et al.Guidelines for performing Mendelian randomization investigations: Update for summer 2023[J].Wellcome Open Res,2023,4:186.
[9] Richmond RC, Davey Smith G.Mendelian randomization: Concepts and scope[J].Cold Spring Harb Perspect Med, 2022,12(1):a040501.
[10] Zheng J, Baird D, Borges MC, et al.Recent developments in Mendelian randomization studies[J].Curr Epidemiol Rep,2017,4(4):330-345.
[11] Power GM, Sanderson E, Pagoni P, et al.Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review[J].Eur J Epidemiol, 2024,39(5):501-520.
[12] Bolhuis K, Mulder RH, de Mol CL, et al.Mapping gene by early life stress interactions on child subcortical brain structures: A genome-wide prospective study[J].JCPP Adv, 2022,2(4):e12113.
[13] Burgess S, Small DS, Thompson SG.A review of instrumental variable estimators for Mendelian randomization[J].Stat Methods Med Res, 2017,26(5):2333-2355.
[14] Miao JP, Gu XY, Shi RZ.COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study[J].Front Cardiovasc Med, 2022,9:974944.
[15] Cupido AJ, Kraaijenhof JM, Burgess S, et al.Genetically predicted neutrophil-to-lymphocyte ratio and coronary artery disease: Evidence from Mendelian randomization[J].Circ Genom Precis Med, 2022,15(1):e003553.
[16] Lü X, Hu Z, Liang F, et al.Causal relationship between ischemic stroke and its subtypes and frozen shoulder: A two-sample Mendelian randomization analysis[J].Front Neurol, 2023,14:1178051.
[17] Bowden J, Holmes MV.Meta-analysis and Mendelian randomization: A review[J].Res Synth Methods, 2019,10(4):486-496.
[18] Bowden J, Davey Smith G, Haycock PC, et al.Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator[J].Genet Epidemiol, 2016,40(4):304-314.
[19] Burgess S, Thompson SG.Interpreting findings from Mendelian randomization using the MR-Egger method[J].Eur J Epidemiol, 2017,32(5):377-389.
[20] Verbanck M, Chen CY, Neale B, et al.Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J].Nat Genet, 2018,50(5):693-698.
[21] 肖乐,叶小姗.重视孤独症谱系障碍发生的神经生物学机制[J].中国儿童保健杂志,2024,32(12):1277-1281.
Xiao L,Ye XS.Emphasizing the neurobiological mechanisms of autism spectrum disorder[J].Chin J Child Health Care, 2024,32(12):1277-1281.(in Chinese)
[22] Nolvi S, Merz EC, Kataja EL, et al.Prenatal stress and the developing brain: Postnatal environments promoting resilience[J].Biol Psychiatry, 2023,93(10):942-952.
[23] Ong LT, Fan SWD.Morphological and functional changes of cerebral cortex in autism spectrum disorder[J].Innov Clin Neurosci, 2023,20(10-12):40-47.
[24] Yoo T, Kim SG, Yang SH, et al.A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum[J].Mol Autism, 2020,11(1):19.
[25] Langen M, Bos D, Noordermeer SD, et al.Changes in the development of striatum are involved in repetitive behavior in autism[J].Biol Psychiatry, 2014,76(5):405-411.
[26] Tian J, Gao X, Yang L.Repetitive restricted behaviors in autism spectrum disorder: From mechanism to development of therapeutics[J].Front Neurosci, 2022,16:780407.
[27] Sato W, Kubota Y, Kochiyama T, et al.Increased putamen volume in adults with autism spectrum disorder[J].Front Hum Neurosci, 2014,8:957.
[28] Tan AP, Ngoh ZM, Yeo SSP, et al.Left lateralization of neonatal caudate microstructure affects emerging language development at 24-months[J].Eur J Neurosci, 2021,54(2):4621-4637.
[29] Estes A, Shaw DW, Sparks BF, et al.Basal ganglia morphometry and repetitive behavior in young children with autism spectrum disorder[J].Autism Res, 2011,4(3):212-220.
[30] Langen M, Schnack HG, Nederveen H, et al.Changes in the developmental trajectories of striatum in autism[J].Biol Psychiatry, 2009,66(4):327-333.
[31] Shiohama T, Ortug A, Warren JLA, et al.Small nucleus accumbens and large cerebral ventricles in infants and toddlers prior to receiving diagnoses of autism spectrum disorder[J].Cereb Cortex, 2022,32(6):1200-1211.
[32] Antonacci C, Buthmann JL, Borchers LR, et al.Nucleus accumbens volume mediates the association between prenatal adversity and attention problems in youth[J].Dev Psychopathol,2025,15:1-13.
[33] Walker LO, Murry N.Maternal stressors and coping stra-tegies during the extended postpartum period: A retrospective analysis with contemporary implications[J].Womens Health Rep, 2022,3(1):104-114.
[34] Beversdorf DQ, Manning SE, Hillier A, et al.Timing of prenatal stressors and autism[J].J Autism Dev Disord, 2005,35(4):471-478.
[35] Chan SY, Low XZ, Ngoh ZM, et al.Neonatal nucleus accumbens microstructure modulates individual susceptibility to preconception maternal stress in relation to externalizing behaviors[J].J Am Acad Child Adolesc Psychiatry, 2024,63(10):1035-1046.
基金
山东省药品临床综合评价项目(2022YZ028);潍坊市卫生健康委员会中医药科研项目(WFZYY2025-3-009)
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