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

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.

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.

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.

The findings provided new genes, pathways, and brain regions to understand the pathology of insomnia.