A cross-tissue transcriptome-wide association study identifies new susceptibility genes for insomnia.

Despite a significant genetic component to insomnia (heritability: 22-25%), the genetic loci that modulate insomnia risk remain limited. We employed the Unified Test for Molecular Markers (UTMOST) for transcriptome-wide association studies (TWAS) across various tissues, integrating summary statistics from a Genome-Wide Association Study (GWAS) of 462,341 European participants with gene expression data from the Genotype-Tissue Expression (GTEx) project. Three validation methods (FUSION, FOCUS, and MAGMA) were used to confirm important genes. Tissue and functional enrichment analyses of insomnia-related single nucleotide polymorphisms (SNPs) were conducted with MAGMA. Conditional and joint analyses, along with fine mapping, were used to enhance our understanding of insomnia's genetic architecture. Mendelian randomization was employed to assess causal associations between significant genes and insomnia. Two novel susceptibility genes, VRK2 and MMRN1, were identified as linked to insomnia risk using four TWAS approaches. Mendelian randomization analysis suggests VRK2 increases the risk of insomnia. Tissue enrichment analyses indicated that insomnia-related SNPs were enriched in specific brain regions, including the cerebellum, frontal cortex (BA9), hypothalamus, and hippocampus. Conditional and joint analyses identified two genomic regions (2p16.1 and 4q22.1). Functional enrichment analyses showed that pathways related to insomnia involve the SMAD2/3 pathway, synaptic function, and oxidative stress. This study identifies two new candidate genes, VRK2 and MMRN1, that may contribute to insomnia risk through neurodevelopment, neuroinflammation, and synaptic function, suggesting potential therapeutic targets.