Abstract: Objective To analyze the causal relationship between circulating amino acid levels and autism spectrum disorder (ASD), in order to provide genetic evidence for precision intervention strategies in ASD. Methods Based on summary data from genome-wide association studies (GWAS) in European populations, a two-sample Mendelian randomization (MR) framework was employed, incorporating 18 381 ASD cases and 27 969 controls.A total of 441 genetic instrumental variables (SNPs) were selected, covering 20 circulating amino acids.The inverse-variance weighted (IVW) method was used as the primary analysis, supplemented by weighted median (WME), MR-Egger regression, and weighted mode (WM) methods to assess causal effects.Sensitivity and pleiotropy were evaluated using Cochran′s Q test and MR-PRESSO. Results The causal analysis revealed no significant association between genetically predicted circulating amino acid levels and ASD risk (IVW P>0.05), this finding was consistent across MR-Egger regression, WME, and WM analysis.This conclusion remained robust after outlier correction via MR-PRESSO.However, Cochran′s Q test indicated significant heterogeneity for lysine (Q=24.037, P=0.045) and leucine (Q=23.713, P=0.049).MR-PRESSO detected horizontal pleiotropy for tryptophan (global P =0.001) and lysine (global P =0.046), but no significant causal associations persisted after outlier correction (corrected tryptophan β=-0.07, P=0.21, lysine β=0.12,P=0.09).The 95% confidence intervals for tryptophan, lysine, methionine, arginine, and threonine were exceptionally wide in MR-Egger regression or WM analysis. Conclusions Genetically predicted circulating amino acid levels show no direct causal relationship with ASD.However, the robustness of results for tryptophan, lysine, methionine, arginine, threonine, and leucine was limited, warranting cautious interpretation.

Key words: autism spectrum disorder, Mendelian randomization, circulating amino acids, causal relationship, genetic instrumental variables

摘要： 目的 分析循环氨基酸水平与孤独症谱系障碍(ASD)的因果关系,为ASD的精准干预策略提供遗传学证据。 方法 基于欧洲人群全基因组关联研究(GWAS)汇总数据,采用两样本孟德尔随机化(MR)框架,纳入18 381例ASD患者和27 969例对照。筛选441个遗传工具变量(SNP),涵盖20种循环氨基酸。采用逆方差加权法(IVW),辅以加权中位数(WME)、MR-Egger回归及加权众数法(WM)评估因果效应,通过Cochran′s Q检验及MR-PRESSO方法验证结果的敏感性和多效性。 结果 因果分析结果显示,遗传预测的循环氨基酸水平与ASD风险无显著因果关联(IVW P＞0.05),这一发现在MR-Egger回归、WME、WM分析中得到验证,经过MR-PRESSO异常值校正同样支持这一结论。但Cochran′s Q检验结果表明赖氨酸(Q=24.037, P=0.045)与亮氨酸(Q=23.713,P=0.049)存在显著异质性。MR-PRESSO检出色氨酸(全局P=0.001)与赖氨酸(全局P=0.046)存在水平多效性,但校正异常值后无显著的因果关联(校正后色氨酸β=-0.07,P=0.21,赖氨酸 β=0.12,P=0.09)。色氨酸、赖氨酸、蛋氨酸、精氨酸、苏氨酸的MR Egger回归或WM 95%CI异常宽泛。 结论 遗传预测的循环氨基酸水平与ASD无直接因果关系,但色氨酸、赖氨酸、蛋氨酸、精氨酸、苏氨酸、亮氨酸的结果稳健性不足,结果需谨慎解释。

关键词: 孤独症谱系障碍, 孟德尔随机化, 循环氨基酸, 因果关系, 遗传工具变量