Joint analysis ofmutations from autism spectrum disorder, schizophrenia, congenital heart disease, and other developmental disorders improves detection power and implicates shared molecular pathways and CNS processes.

This study looked at genetic changes in over 43,000 families affected by autism, developmental delays, heart conditions, and schizophrenia. Researchers found that these conditions share some of the same genetic risk factors, particularly autism and developmental delays. The shared genes mainly affect brain cell communication and brain development. This suggests these conditions may have common biological causes, which could help explain why they sometimes occur together in families.

This large-scale genetic study analyzed rare exonic variants in 43,287 case trios across autism spectrum disorder (ASD), undiagnosed developmental disorders (UDD), intellectual disability (ID), congenital heart disease (CHD), and schizophrenia (SCZ). Using Bayesian integrative analysis, researchers identified 180 candidate risk genes for ASD, 315 for UDD/ID, 49 for CHD, and 47 for SCZ. The study revealed shared genetic risk factors between conditions, with ASD-UDD/ID and ASD-SCZ shared genes predominantly involving synaptic function and epigenetic modification pathways. CHD-ASD shared genes were associated with cell cycle processes, while CHD-UDD/ID genes involved cardiac development.

Expression analysis showed ASD-UDD/ID risk genes were elevated in interneurons and pyramidal cells, suggesting common neurobiological mechanisms across these neurodevelopmental conditions.

Results support genetic screening approaches that consider multiple neurodevelopmental conditions simultaneously. Shared pathways suggest interventions targeting synaptic function and epigenetic mechanisms may benefit multiple conditions. Findings could inform genetic counseling for families with complex developmental presentations.

Study focuses on rare exonic variants only, potentially missing other genetic contributions. Functional validation of candidate genes not provided. Clinical phenotype heterogeneity within diagnostic categories not addressed. Posterior probability threshold may miss some genuine risk genes.

Rare exonic variant studies have previously implicated overlapping risk genes and pathways for autism spectrum disorder (ASD), severe, undiagnosed developmental disorders (UDDs), intellectual disability (ID), congenital heart disease (CHD), and schizophrenia (SCZ). Here, we use a two-trait Bayesian integrative analysis approach on 43 287 ASD, UDD/ID, CHD, and SCZ case trios to increase statistical power for gene discovery and to identify shared risk genes. At a posterior probability > 0.80, we identified 180 candidate risk genes for ASD, 315 for UDD/ID, 49 for CHD, and 47 for SCZ, including genes not previously reported, and also detected shared risk genes in pair-wise analyses. Gene set enrichment analysis of the ASD-UDD/ID, ASD-SCZ, and UDD/ID-SCZ shared risk genes overwhelmingly implicated gene sets associated with the synapse and epigenetic modification, while CHD-ASD shared risk genes were enriched in cell cycle phase transition gene sets, and CHD-UDD/ID shared risk genes implicated cardiac development.

ASD-UDD/ID risk genes had elevated expression in interneurons and pyramidal cells, while ASD-UDD/ID and CHD-UDD/ID shared risk genes showed elevated connectivity in protein-protein interaction networks. Leveraging information across disorders with genetic overlap, both to increase power for candidate risk gene discovery and also as a method to elucidate shared genetic mechanisms.