Association between plasma proteome and childhood neurodevelopmental disorders: A two-sample Mendelian randomization analysis

Background: Childhood neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS), comprise a major cause of health-related disabilities in children. However, biomarkers towards pathogenesis or novel drug targets are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on ASD, ADHD, and TS using the two-sample Mendelian Randomization (MR) approach. Methods: Genetic associations with 2994 plasma proteins were selected as exposures and genome-wide association data of ASD, ADHD, TS were utilized as outcomes. MR analyses were carried out using the inverse-variance weighted method, and the MR-Egger and weighted median methods were used for sensitivity analysis. Findings: Using single-nucleotide polymorphisms as instruments, the study suggested increased levels of MAPKAPK3 (OR: 1.09; 95% CI: 1.05–1.13; P = 1.43 × 10⁻⁶) and MRPL33 (OR: 1.07; 95% CI: 1.04–1.11; P = 5.37 × 10⁻⁶) were causally associated with a higher risk of ASD, and increased MANBA level was associated with a lower risk of ADHD (OR: 0.91; 95% CI: 0.88–0.95; P = 8.97 × 10⁻⁶). The causal associations were robust in sensitivity analysis, leave-one-out analysis and Multivariable MR, and no pleiotropy was observed. No significant risk protein was identified for TS. Interpretation: The study findings support the idea that the MAPK/ERK signaling pathway and mitochondrial dysfunction are involved in the pathogenesis of ASD, while a deficiency in beta-mannosidase might play a role in the development of ADHD.