Causal association between mTOR-dependent circulating protein levels and autism spectrum disorder: a Mendelian randomization study

Abstract

Abstract Background Overactivation of the mTOR signaling pathway is a critical mechanism in the pathogenesis of autism spectrum disorder (ASD). However, the causal relationships between key molecules downstream of the mTOR signaling pathway and ASD remains unclear. This study aimed to explore the causal associations between seven mTOR-dependent circulating protein levels and ASD. Methods Instrumental variables (IVs) used as proxies for mTOR-dependent circulating protein levels were derived from the proteomics-GWAS INTERVAL study (3,301 participants) and a serum protein GWAS study in an Icelandic population (5,368 participants). Two ASD summary datasets were obtained from a meta-analysis study of ASD GWAS datasets (22,196 cases and 32,504 controls) and the FinnGen Consortium (646 cases and 301,879 controls), respectively. We applied two-sample Mendelian randomization (MR) to assess whether there is a causal association between seven mTOR-dependent circulating protein levels and ASD. Furthermore, validation analyses of positive exposures in the discovery cohort were performed to confirm the reliability of the findings. Results In this two-sample MR study, plasma PKCα level was found to be causally related to ASD in both the discovery cohort (IVW: OR = 1.15, 95% CI = 1.05–1.25, p = 0.002) and the validation cohort (IVW: OR = 1.14, 95% CI = 1.02–1.27, p = 0.017). Conclusions There was a causal association between the plasma level of PKCα and ASD, suggesting PKCα as a potential biomarker for the prevention, monitoring and treatment of ASD. However, whether PKCα can play a role in the clinical management of ASD remains to be demonstrated in future research.