A Combined Analysis of Genetically Correlated Traits Identifies Genes and Brain Regions for Insomnia

Aims: Previous studies have inferred that there is a strong genetic component in insomnia. However, the etiology of insomnia is still unclear. This study systematically analyzed multiple genome-wide association study (GWAS) data sets with core human pathways and functional networks to detect potential gene pathways and networks associated with insomnia.Methods: We used a novel method, multitrait analysis of genome-wide association studies (MTAG), to combine 3 large GWASs of insomnia symptoms/complaints and sleep duration. The i-Gsea4GwasV2 and Reactome FI programs were used to analyze data from the result of MTAG analysis and the nominally significant pathways, respectively.Results: Through analyzing data sets using the MTAG program, our sample size increased from 113,006 subjects to 163,188 subjects. A total of 17 of 1,816 Reactome pathways were identified and showed to be associated with insomnia. We further revealed 11 interconnected functional and topologically interacting clusters (Clusters 0 to 10) that were associated with insomnia. Based on the brain transcriptome data, it was found that the genes in Cluster 4 were enriched for the transcriptional coexpression profile in the prenatal dorsolateral prefrontal cortex ( P = 7 × 10 −5 ), inferolateral temporal cortex ( P = 0.02), medial prefrontal cortex ( P < 1 × 10 −5 ), and amygdala ( P < 1 × 10 −5 ), and detected RPA2, ORC6, PIAS3, and PRIM2 as core nodes in these 4 brain regions.Conclusions: The findings provided new genes, pathways, and brain regions to understand the pathology of insomnia.