Neurodevelopment as a shared genetic etiology linking sleep-related phenotypes and psychiatric disorders: a genome-wide pleiotropic analysis.

Comorbidity and mutual transformation between psychiatric disorders (including autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorder, post-traumatic stress disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and anxiety disorders) and sleep disorders are common, with circadian rhythm disruption considered a potential biological basis, and neurodevelopmental abnormalities seemingly playing a key role. However, the extent to which shared genetic determinants contribute to these associations remains unclear. Extensive genetic correlations and overlaps were observed between sleep-related phenotypes and psychiatric disorders, with Mendelian randomization analysis further suggesting vertical pleiotropy in 21 of these pairs. Pleiotropic analysis identified 71,733 pleiotropic single nucleotide variants, 718 pleiotropic loci, and 226 co-located loci, with 1,225 candidate pleiotropic genes enriched in phenotypes related to neurodevelopment and brain tissues. A total of 187 candidate pleiotropic genes were screened through Polygenic Priority Score or summary data-based Mendelian Randomization. Pathway enrichment analysis further highlighted biological pathways primarily involving neurodevelopment, synaptic structure, and rhythmic behaviors. Additionally, key hub genes such as HNRNPK, GNL3 and YWHAE exhibited peak expression during early prenatal stages, followed by a decline or plateau throughout life. This study reveals a broad spectrum of pleiotropic genes shared between psychiatric disorders and sleep-related phenotypes, highlighting neurodevelopment as a key mechanism underlying their comorbidity. These findings provide new insights into potential therapeutic targets for these conditions.