The prevalence of sleep disorders is increasing worldwide, prompting greater efforts to understand the biological mechanisms underlying sleep. Despite the growing interest in this area, a continuous transcriptome analysis for studying sleep quality is still lacking. This study performed a regression analysis of the Pittsburgh sleep quality index (PSQI) from the blood transcriptome to identify marker genes associated with sleep quality. In this cohort study, sleep quality scores were defined for 100 participants, and molecular properties associated with the scores were analyzed using blood transcriptome analysis. Gene expression and pathway enrichment analyses revealed that immune-related dysregulation was prominently associated with sleep quality. To understand the genetic influences on our observations, a genome-wide association study (GWAS) was conducted to examine the relationship between sleep quality and immune indicators. The results revealed a relationship between sleep and the immune system and confirmed a genetic correlation. Our study provides valuable insights into the complex interplay between the genetic and environmental factors that determine sleep quality and their impact on overall health.