Cell-specific variant-to-gene mapping identifies conserved neural and glial regulators of sleep

Area of Science:

• Neuroscience
• Genetics
• Sleep Research

Background:

• Excessive daytime sleepiness (EDS) is a complex trait with an unknown genetic basis.
• Genome-wide association studies (GWAS) have identified genomic loci linked to EDS, but causal genes and cell types remain unidentified.

Purpose of the Study:

• To identify causal genes and cell types underlying EDS GWAS loci.
• To establish a framework for connecting non-coding GWAS variants to effector genes influencing sleep.

Main Methods:

• Utilized chromatin-based variant-to-gene mapping in human neural and glial cell lines.
• Performed cell type-specific RNAi knockdown in Drosophila to assess gene function in vivo.
• Validated findings in zebrafish using CRISPR-mediated gene editing.

Main Results:

• Implicated candidate effector genes at EDS GWAS loci using variant-to-gene mapping.
• Confirmed cell-specific regulation of sleep by GWAS-implicated genes in Drosophila.
• Identified AP3B2 (ruby) as a conserved regulator of sleep, functioning in astrocyte-like glia to increase sleep duration.

Conclusions:

• Variant-to-gene mapping successfully predicted cell-type-specific gene function for complex sleep traits.
• AP3B2 is a novel, evolutionarily conserved glial regulator of sleep and arousal.
• This approach provides a generalizable method for linking non-coding GWAS variants to conserved sleep regulators.