Convergent coexpression reveals shared biological mechanisms underlying common and rare variant risk in six neuropsychiatric disorders

Abstract

Genome-wide association studies (GWAS) and large-scale rare variant burden analyses have identified both common and rare loss-of-function variants associated with neuropsychiatric disorders. Yet, the shared biological processes influenced by both classes of variation remain poorly characterized. In this study, we utilized transcriptomic data from 933 post-mortem brain samples to identify genes that show convergent coexpression with GWAS and rare variant burden risk genes across six neuropsychiatric disorders. Despite largely distinct sets of significant risk genes from GWAS and rare variant burden studies, we found a significant overlap in their convergently coexpressed genes. These convergent genes showed enrichment for common and rare variant heritability and highlighted key biological pathways and cell-type markers impacted by both types of genetic variation. Compared to genes coexpressed with one variant class, shared convergent genes exhibited stronger evolutionary constraint and greater enrichment for known drug targets, underscoring their potential therapeutic relevance. Collectively, our results establish a systematic and generalizable framework for integrating coexpression data with genetic risk to reveal transcriptional programs supported by both common and rare variant evidence, offering mechanistic insights into neuropsychiatric diseases.