Integrative analysis of genome-wide association study and brain region related enhancer maps identifies biological pathways for insomnia

Insomnia is a common sleep disorder whose genetic mechanism remains unknown. The aim of this study is to identify novel genes, gene enrichment sets and enriched tissue/cell types for insomnia considering the differences across different brain regions. We conducted an integrative analysis of genome-wide association study (GWAS) and brain region related enhancer maps. Summary data was derived from a large-scale GWAS of insomnia, involving 113,006 unrelated individuals. The chromosomal enhancer maps of 6 brain regions were then aligned with the GWAS summary data to obtain the association testing results of enhancer regions for insomnia. Gene prioritization, tissue/cell and pathway enrichment analysis were implemented by Data-driven Expression Prioritized Integration for Complex Traits (DEPICT) tool. We identified multiple cross-brain regions or brain-region specific prioritized genes for insomnia, such as MADD (P = .0013 in angular gyrus), PPP2R3C (P = .0319 in cingulate gyrus), CASP9 (P = .0066 in angular gyrus and P = .0278 in hippocampus middle), PLEKHM2 (P = .0032 in angular gyrus, P = .0052 in anterior caudate, P = .0385 in cingulate gyrus and P = .0011 in inferior temporal lobe). This study also detected a group of insomnia associated biological pathways within multiple or specific brain regions, such as REACTOME_SIGNALING_BY_NOTCH and KEGG_GLYCEROPHOSPHOLIPID_METABOLISM. Our results showed that insomnia associated genes were significantly enriched in neural stem cells. Our results highlight a set of potential points, particularly neural stem cells, for subsequent biological studies for insomnia.