Single-cell brain expression–guided causal analysis identifies GFM1 as a protective factor in insomnia risk

Background: Insomnia is a common and heritable neurological condition that lacks clearly defined causal molecular drivers. Identifying brain cell–specific genes with protective effects may uncover new therapeutic targets for sleep-related disorders. Methods: We integrated brain single-cell gene expression profiles with insomnia genome-wide association data from the UK Biobank (109,548 cases, 277,440 controls). Using Wald ratio–based Mendelian randomization (MR), we estimated the causal effects of cell type-specific gene expression on insomnia. Significant genes were evaluated via Bayesian colocalization and Steiger filtering to confirm shared causal variants and correct expression-to-trait directionality. Independent replication used the FinnGen cohort (6,776 cases, 490,763 controls). Phenotype specificity and anatomical expression were assessed using phenome-wide association studies (PheWAS) and The Human Protein Atlas. Results: Among multiple cell type–specific associations, GFM1 emerged as a protective gene for insomnia in excitatory neurons (OR=0.90, FDR=0.0109), and was independently replicated in FinnGen (OR=0.77, P=0.0019). Colocalization analysis supported a shared causal variant at the GFM1 locus (PP.H4=0.717), and Steiger directionality filtering confirmed the causal path from gene expression to phenotype. PheWAS showed phenotype specificity without evidence of horizontal pleiotropy. GFM1 was predominantly expressed in sleep-regulating brain regions such as the cerebral cortex, midbrain, and hypothalamus, supporting its functional relevance in sleep biology. Conclusion: This integrative analysis identifies GFM1 as a robust, brain cell–specific protective gene for insomnia, with cross-dataset replication and functional support from colocalization, PheWAS, and expression atlases. Given its role in mitochondrial translation, GFM1 may represent a novel target for interventions aimed at sleep-related neurological conditions.