From single nucleotide variations to genes: identifying the genetic links between sleep and psychiatric disorders

Abstract

Study Objectives Sleep disorders and psychiatric disorders frequently coexist and interact, yet the shared genetic basis linking these two domains remains poorly understood. Methods We investigated the genetic correlation and overlap between seven sleep/circadian traits and three psychiatric disorders at the level of genome-wide association studies (GWAS), utilizing LDSC, HDL, and GPA. To identify potential polygenic single nucleotide variations (SNVs) within each trait pair, we used PLACO, while gene-level analyses were performed using MAGMA and POPS. Furthermore, the functions and biological mechanisms, enriched phenotypes, tissues, cellular features, and pathways were thoroughly investigated using FUMA, deTS, and enrichment analyses at the biological pathway level. Results Our study revealed extensive genetic associations and overlaps in all 21 trait pairs. We identified 18 494 SNVs and 543 independent genomic risk loci, with 113 confirmed as causative through colocalization analysis. These loci collectively spanned 196 unique chromosomal regions. We pinpointed 43 distinct pleiotropic genes exhibiting significant enrichment in behavioral/physiological phenotypes, nervous system phenotypes, and brain tissue. Aberrations in synaptic structure and function, neurogenesis and development, as well as immune responses, particularly involving the MAPK pathway, emerged as potential underpinnings of the biology of sleep/circadian traits and psychiatric disorders. Conclusions We identified shared loci and specific sets of genes between sleep/circadian traits and psychiatric disorders, shedding light on the genetic etiology. These discoveries hold promise as potential targets for novel drug interventions, providing valuable insights for the development of therapeutic strategies for these disorders.