Multi-omics integration identifies the common genetic basis for congenital heart disease and autism spectrum disorder

Congenital Heart Disease (CHD) and Autism Spectrum Disorders (ASD) are prevalent and complex conditions, and growing evidence suggests that they share overlapping genetic underpinnings. In this study, we systematically integrated datasets to elucidate the common genetic mechanisms between CHD and ASD. We identified 73 overlapping genes between the two disorders, of which 23 were highlighted as key shared candidate genes. Functional analyses revealed previously reported genes NOTCH1, PTPN11, and SMAD4 as central nodes in the protein–protein interaction network, predominantly involved in developmental pathways such as Notch, TGF-β, and Wnt signaling. SMR analysis identified UPF2 and CHD7 as key risk genes, with ZNF83 and ZNF584 implicated as transcriptional regulators. Single-cell trajectories revealed dynamic expression of CHD7 during development, linking its dysregulation to disease progression. Mechanistically, UPF2 dysfunction leads to toxic transcript accumulation, impairing heart and brain development. Collectively, our findings provide a genetic framework for understanding CHD and ASD comorbidity and offer new insights into shared molecular etiology and potential biomarkers for early diagnosis and therapeutic intervention.