孟德尔随机化分析免疫细胞表型与孤独症谱系障碍的因果关联

doi:10.6040/j.issn.1671-7554.0.2025.0193

摘要/Abstract

摘要： 目的探讨免疫细胞表型与孤独症谱系障碍(autism spectrum disorder, ASD)之间的因果关系。方法采用双向双样本孟德尔随机化(mendelian randomization, MR)分析,利用欧洲人群全基因组关联研究(genome-wide association studies, GWAS)的公开遗传数据,以单核苷酸多态性(single nucleotide polymorphisms, SNPs)作为工具变量,主要采用逆方差加权法(inverse variance weighted, IVW)进行因果效应分析,并辅以MR-Egger回归、加权中位数、加权模式和简单模式等方法进行验证。为控制多重比较带来的假阳性结果,采用Benjamini-Hochberg方法进行错误发现率(false discovery rate, FDR)校正。通过Cochran Q检验评估工具变量的异质性,运用MR-Egger截距分析和MR-PRESSO全局测试评估水平多效性,并采用留一法进行敏感性分析。结果研究共纳入13 092个SNPs作为工具变量。经FDR校正后,未发现免疫细胞表型与ASD存在统计学显著关联(P_FDR>0.05)。然而,在未经校正的分析中,6种低P值表型仍值得讨论,具体包括:CD8⁺T细胞在白细胞中百分比(OR=1.099,95%CI:1.039~1.163,P_IVW=0.001)、CD20在IgD⁺CD38^-B细胞中的表达水平(OR=1.064,95%CI:1.019~1.110,P_IVW=0.005)和CD45在未成熟MDSCs中的表达水平(OR=1.056,95%CI:1.021~1.093,P_IVW=0.001)与ASD风险呈正相关;而CD45在HLA DR⁺T细胞中的表达水平(OR=0.945,95%CI:0.906~0.986,P_IVW=0.009)、CD14在CD33⁺HLA DR⁺CD14dim中的表达水平(OR=0.955,95%CI:0.925~0.987,P_IVW=0.006)和CD25在CD4调节性T细胞中的表达水平(OR=0.963,95%CI:0.939~0.989,P_IVW=0.005)可能对ASD具有保护作用。所有分析均未发现显著的水平多效性或异质性,敏感性分析表明结果稳健。反向MR分析未发现ASD对以上免疫细胞表型的显著影响。结论本研究提示特定免疫细胞表型可能与ASD发病风险存在潜在因果关系,为未来探索ASD的免疫相关生物标志物和潜在治疗靶点提供了研究方向。

关键词: 孤独症谱系障碍, 免疫细胞, 免疫细胞表型, 孟德尔随机化

Abstract: Objective To explore the causal relationship between immune cell phenotypes and autism spectrum disorder. Methods The present study utilised a bidirectional two-sample mendelian randomization analysis. The present study utilised publicly available genetic data from genome-wide association studies(GWAS)in European populations. Single-nucleotide polymorphisms(SNPs)were utilised as instrumental variables(IVs). The causal effect analysis was primarily executed using the inverse variance weighted(IVW)method, with additional validation conducted via MR-Egger regression, weighted median, weighted mode, and simple mode. In order to control for the possibility of false positive results resulting from multiple comparisons, false discovery rate(FDR)correction was performed using the Benjamini-Hochberg method. The heterogeneity of the IVs was assessed by the Cochran Q-test, while the horizontal multiple validity was tested using the MR-Egger intercept analysis and the MR-PRESSO global test. Finally, sensitivity analyses were performed using the leave-one-out method. Results A total of 13,092 SNPs were included in the study as IVs. Following FDR correction(P_FDR>0.05), no statistically significant association was identified between immune cell phenotypes and ASD. Nevertheless, six low P-value phenotypes merit further discussion in the uncorrected analysis. Specifically, the percentage of CD8⁺T cells in leukocytes(OR=1.099,95%CI:1.039-1.163, P_IVW=0.001), the expression level of CD20 in lgD⁺CD38^-B cells(OR=1.064, 95%CI:1.019-1.110, P_IVW=0.005)and the expression level of CD45 in immature MDSCs(OR=1.056,95%CI: 1.021-1.093, P_IVW=0.001)may incease ASD risk. In addition, CD45 expression level in HLA DR⁺ T cells(OR=0.945, 95%CI:0.906-0.986, P_IVW=0.009), CD14 expression level in CD33⁺HLA DR⁺CD14 dim(OR=0.955, 95%CI:0.925-0.987, P_IVW=0.006)and CD25 expression level in CD4 regulatory T cells(OR=0.963, 95% CI:0.939-0.989, P_IVW=0.005)may have a protective effect against ASD. The analyses did not reveal any substantial horizontal pleiotropy or heterogeneity. Sensitivity analyses indicated robust results. Conversely, reverse MR analysis did not demonstrate a substantial impact of ASD on the aforementioned immunophenotype. Conclusion The present study suggests that specific immune cell phenotypes may have a potential causal relationship with the risk of ASD development, and provides a research direction for future exploration of immune-related biomarkers and potential therapeutic targets for ASD.

Key words: Autism spectrum disorder, Immune cell, Immune cell phenotype, Mendelian randomization

中图分类号:

R749.94

吴志晓,赵红洋. 孟德尔随机化分析免疫细胞表型与孤独症谱系障碍的因果关联[J]. 山东大学学报 (医学版), 2026, 64(3): 83-92.

WU Zhixiao, ZHAO Hongyang. Mendelian randomization analysis of causal associations between immune cell phenotypes and the risk of autism spectrum disorders[J]. Journal of Shandong University (Health Sciences), 2026, 64(3): 83-92.

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