Impact of interaction between individual genomes and preeclampsia on the severity of autism spectrum disorder symptoms.

OBJECTIVES

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Prior research suggests that genetic susceptibility and environmental exposures, such as maternal preeclampsia (PE) during pregnancy, play key roles in ASD pathogenesis. However, the specific effects of the interaction between genetic and environmental factors on ASD phenotype severity remain unclear. This study aims to investigate how interactions between de novo variants (DNVs) and common variants in individual genomes and PE exposure affect ASD symptom severity by constructing a gene-environment model.

METHODS

Phenotypic data were obtained from the Simons Simplex Collection (SSC) database for idiopathic ASD patients aged 4-18. Subjects were divided based on maternal PE status: PE (exposed) and PE (unexposed) groups. Those without DNVs were divided into DNVPE and DNVPE groups, and those with DNVs into DNVPE and DNVPE groups. Based on polygenic risk scores (PRS), subjects below the median were classified into PRSPE and PRSPE groups, and those at or above the median into PRSPE and PRSPE groups. Core ASD phenotypic assessed included adaptive and cognitive abilities, social reciprocity, language and communication skills, and repetitive behaviors. Adaptive and cognitive abilities were scored using adaptive behavior composite scores from the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), along with verbal intelligence quotient (VIQ) and nonverbal intelligence quotient (NVIQ) scores from the SSC database. Social reciprocity abilities were measured using the social domain scores from the Autism Diagnostic Interview-Revised (ADI-R SD), social affective domain scores from the Autism Diagnostic Observation Schedule (ADOS SA), and normalized scores from the Social Responsiveness Scale (SRS). Language and communication abilities were assessed through verbal communication domain (ADI-R VC), nonverbal communication domain (ADI-R NVC) scores from ADI-R, and the communication and social domain scores from ADOS (ADOS CS). Repetitive behaviors were measured using the restricted and repetitive behaviors domain scores from ADI-R (ADI-R RRB), the repetitive domain scores from ADOS (ADOS REP), and the overall scores from the Repetitive Behavior Scale-Revised (RBS-R). Linear regression models were constructed to explore the impact of PE exposure and its interaction with individual genomes (including DNVs and common variants) on core ASD phenotypes. Additionally, ASD candidate genes associated with DNVs underwent gene ontology (GO) enrichment analysis via Metascape, and temporal and spatial gene expression patterns were examined using RNA sequencing (RNA-seq) data from the BrainSpan database.

RESULTS

A total of 2 439 ASD patients with recorded DNV information and confirmed PE exposure status were included, with 146 in the PE group and 2 293 in the PE group. There was a trend toward differences between these two groups in SRS (=2.01, =0.08) and ADI-R NVC (=-0.62, =0.09). Among the 2 439 participants, there were 1 454 in the DNVPE group, 90 in the DNVPE group, 839 in the DNVPE group, and 56 in the DNVPE group. Analysis of the main effect of PE exposure showed significant impacts on SRS (=3.71, =0.01) and RBS-R (=4.54, =0.05). Interaction analysis between DNVs and PE exposure revealed a trend toward significance in SRS (=-4.17, =0.06). In the 2 236 participants with available PRS data, there were 1 033 in the PRSPE group, 72 in the PRSPE group, 1 069 in the PRSPE group, and 62 in the PRSPE group. Analysis of the main effect of PE exposure showed significant impacts on SRS (=4.32, <0.001) and RBS-R (=5.87, =0.02). The interaction between PRS and PE exposure showed significant effects on SRS (=-4.90, =0.03) and ADI-R NVC (=-1.43, =0.04), with trends in NVIQ (=9.61, =0.08) and RBS-R (=-6.20, =0.08). Additionally, DNV-enriched genes in PE-exposed patients were associated with regulatory of epithelial-to-mesenchymal transition and DNA-binding transcription factor activity. Temporal and spatial expression pattern analysis indicated that genes enriched in these regulatory processes showed higher expression levels prenatally compared to postnatally.

CONCLUSIONS

PE exposure, an environmental factor influencing ASD, is associated with increased ASD symptom severity. The interaction of PE exposure with genetic factors is crucial in modulating ASD phenotypes. Among PE-exposed individuals, ASD patients with high genetic risk for common variants may show improvements in social reciprocity and communication skills. In contrast, while DNVs may also aid in symptom improvement, their impact is less pronounced than that of common variants. These differences suggest that under similar PE exposure conditions, ASD patients with DNVs or high-risk common variants may exhibit varying degrees of symptom changes. ASD pathology research should consider the combined influence of genetic and environmental factors.