Cross-trait clustering of sub-threshold sleep genetic signals identifies EGR2 as a conserved regulator of sleep

Abstract

Idiopathic hypersomnia (IH) is a highly heritable sleep disorder characterized by excessive daytime sleepiness, yet few genetic pathways contributing to hypersomnolence have been identified. To expand genetic discovery beyond the limited number of genome-wide significant loci associated with sleepiness-related traits, we applied multi-trait clustering to sleep-associated genetic variation that did not reach conventional significance thresholds. Integration with our cell-type-specific variant-to-gene mapping prioritized candidate effector genes for cross-species functional screening. Among the strongest candidates was EGR2, which emerged as a distal effector gene at the ADO-EGR2 locus in neurons. Neuronal knockdown of the Drosophila EGR2 ortholog stripe increased sleep duration and sleep consolidation, while mutation of zebrafish egr2 orthologs similarly increased sleep. Together, these findings demonstrate that sleep-regulatory pathways can be identified from genetic signals below conventional significance thresholds and establish EGR2 as a conserved regulator of sleep across species.