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A cross-tissue transcriptome-wide association study identifies new susceptibility genes for insomnia
Li Li1, Dongjin Wu1, Cuiping Zhang2
1Department of Anesthesiology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People's Republic of China.
Journal of Neurophysiology
|January 2, 2025
Summary
Researchers identified two new genes, VRK2 and MMRN1, linked to insomnia risk using transcriptome-wide association studies (TWAS). Mendelian randomization confirmed VRK2
Area of Science:
- Genetics
- Neuroscience
- Genomics
Background:
- Insomnia has a significant genetic component, but specific genetic risk factors are not well understood.
- Previous studies have identified limited genetic loci associated with insomnia risk.
Purpose of the Study:
- To identify novel genetic loci associated with insomnia risk.
- To investigate the genetic architecture of insomnia using transcriptome-wide association studies (TWAS).
- To explore the causal relationships between identified genes and insomnia.
Main Methods:
- Transcriptome-wide association studies (TWAS) integrating GWAS summary statistics with GTEx gene expression data.
- Utilized four TWAS approaches (UTMOST, FUSION, FOCUS, MAGMA) for gene identification and validation.
- Employed Mendelian randomization, tissue/functional enrichment, and conditional/joint analyses.
Main Results:
- Identified two novel insomnia susceptibility genes: VRK2 and MMRN1.
- Mendelian randomization suggested VRK2 causally increases insomnia risk.
- Discovered enrichment of insomnia-related SNPs in brain regions like the cerebellum and frontal cortex, and pathways including SMAD2/3 signaling and oxidative stress.
Conclusions:
- VRK2 and MMRN1 are novel candidate genes contributing to insomnia risk.
- Findings implicate neurodevelopment, neuroinflammation, and synaptic function in insomnia's genetic basis.
- Identified potential therapeutic targets for insomnia treatment.
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