基于孟德尔随机化分析探讨儿童皮质下脑结构与孤独症谱系障碍的因果关系

Causal relationship between subcortical brain structures and autism spectrum disorder in children based on Mendelian randomization

摘要

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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基金资助

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)