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Updated: Apr 28, 2026
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Plasma proteome and autism spectrum disorder: Integrative proteome-wide Mendelian randomization with clinical
Lihong Wang1, Tianci Liu2, Lianhu Yu1
1Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Background:
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with incompletely elucidated underlying biological mechanisms. Circulating proteins serve as an intermediate molecular layer linking genetic variation to downstream biological processes. This study aimed to systematically investigate the causal associations between the plasma proteome and ASD risk, followed by multi-omic and clinical validation.
Method:
Two-sample Mendelian randomization (MR) was performed to screen 1124 plasma proteins for potential causal links with ASD. Genetically prioritized proteins were further verified using Bayesian colocalization analysis, tissue expression profiling (GTEx), transcriptomic validation (GEO), and co-expression network analyses. In a retrospective cohort of 100 children with ASD, serum concentrations of inflammatory cytokines (IL-6, IL-1β, IL-8, IL-10, TNF-α, IL-2R) and brain injury markers (NSE, S100β) were measured.
Results:
MR analysis identified 23 plasma proteins nominally associated with ASD risk. After correction for multiple testing, MR identified three proteins associated with ASD risk: MICA (OR = 0.964, protective), SERPIND1 (heparin cofactor II; OR = 0.897, protective), and MAPKAPK3 (OR = 1.046, risk-increasing). Genetically predicted MAPKAPK3 showed moderate evidence of colocalization with ASD (PP·H4 = 0.51), suggesting a shared causal variant. Multi-omic analyses indicated that MAPKAPK3 is broadly expressed in brain tissues, significantly upregulated in the ASD cortex, and tightly co-expressed with inflammation-related genes. Clinically, severe ASD was associated with elevated serum levels of IL-6, IL-1β, and IL-8; IL-1β level were positively correlated with the severity of ASD symptoms.
Conclusions:
Integrative evidence from genetic, transcriptomic, network, and clinical analyses supports the involvement of immune-inflammatory pathways in ASD pathogenesis. The MAPKAPK3-centered inflammatory signaling emerges as a genetically supported mechanistic axis, which prioritizing for future functional studies and biomarker development.
