The brain’s default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. However, the genetic basis linking sociability with DMN function remains underexplored. This study aimed to elucidate the shared genetics and causal relationship between sociability and DMN-related resting-state functional MRI (rs-fMRI) traits.

We conducted a comprehensive genomic analysis using large-scale genome-wide association study (GWAS) summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N = 34,691–342,461). We performed global and local genetic correlations analyses and bi-directional Mendelian randomization (MR) to assess shared and causal effects. We prioritized genes influencing both sociability and rs-fMRI traits by combining expression quantitative trait loci MR analyses, the CELLECT framework – integrating single-nucleus RNA sequencing (snRNA-seq) data with GWAS – and network propagation within a protein–protein interaction network.

Significant local genetic correlations were identified between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the cingulate and angular/temporal cortices. MR analyses suggested potential causal effects of sociability on 12 rs-fMRI traits. Seventeen genes were highly prioritized, with LINGO1, ELAVL2, and CTNND1 emerging as top candidates. Among these, DRD2 was also identified, serving as a robust internal validation of our approach.

By combining genomic and transcriptomic data, our gene prioritization strategy may serve as a blueprint for future studies. Our findings can guide further research into the biological mechanisms underlying sociability and its role in the development, prognosis, and treatment of neuropsychiatric disorders.