Detection of Pleiotropic Genetic Factors and Critical Brain Cell Types Linking Insomnia with Psychiatric Disorders

Abstract Insomnia and psychiatric disorders exhibit frequent comorbidity and heritability, yet their shared genetic architecture and neurobiological mechanisms remain unclear. This study investigated genetic overlap, pathways, and brain cell types linking insomnia with 12 psychiatric disorders using genome-wide association study (GWAS) data (insomnia: Neff = 314,149; psychiatric disorders: Neff = 12,783 - 449,855). Significant genetic correlations were identified between insomnia and seven psychiatric conditions: attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depression (MD), and schizophrenia (SCZ). Cross-trait analyses revealed 70 shared loci (97 candidate SNPs), including novel associations: 7 with ADHD, 6 with AN, 3 with ANX, 3 with ASD, 5 with BD, 15 with MD, and 19 with SCZ. Pathway enrichment highlighted GABAergic synapse signaling as a key mechanism underlying these comorbidities. Single-cell RNA sequencing analysis of 36 brain cell types implicated eight cortical neuron subtypes: four GABAergic interneurons and four glutamatergic neurons. Among 71 genes mapped to shared loci, 33 exhibited significant expression in these cell types, with 12 prioritized as potential therapeutic targets. These findings underscore shared genetic foundations between insomnia and psychiatric disorders, centered on cortical GABA-glutamate circuitry, and identify candidate pathways for mitigating comorbid conditions. This integrative approach bridges genetic epidemiology with neurobiology, offering insights into transdiagnostic mechanisms and precision treatment strategies.