Dissecting the genetic architecture of circadian rhythms in human tissues using a quantitative circadian deviation score

Circadian rhythms influence various physiological and behavioral processes, including sleep, metabolism, and immune response. Although key regulatory factors of biological clocks have been identified and genome-wide association studies have pinpointed some genetic variants linked to sleep traits, the genetic architecture underlying circadian rhythms remains incompletely understood. Here, we introduce the circadian deviation score, a novel quantitative trait that measures circadian disruption at the molecular level. Derived from gene expression levels of thousands of circadian genes across Human tissues, this score helps identify tissue-specific genetic influences on circadian rhythms. Our analysis reveals 654 SNPs, which we named Circ-SNPs, associated with global circadian disruption at the expression level. These include previously known SNPs Linked to insomnia, chronotype, and circadian rhythm, as well as new SNPs that enhance understanding of circadian regulation. Most Circ-SNPs exhibit significant associations with the circadian deviation score in the small intestine and adrenal gland, with about 19.4% situated on the X chromosome, highlighting sex-specific differences in circadian disorders. Circ-SNPs often reside near the 3′ end of transcripts, indicating their potential regulatory roles, particularly in post-transcriptional processes. The genes harboring Circ-SNPs, which we named Circ-regulators, are enriched for known circadian traits. DrugBank analysis shows 18 of 122 protein-coding Circ-regulators are targetable by 163 existing drugs, including six approved for sleep disorders. Our findings highlight the potential for repurposing existing drugs to treat circadian-related disorders and provide a deeper understanding of the genetic components of circadian rhythms and sleep disorders.