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
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