Allele-Specific Methylation Links Non-coding Variant of rs2280906 to MYOM2 Regulation in Schizophrenia

Schizophrenia (SCZ) is a complex polygenic disorder influenced by genetic, epigenetic, and environmental factors. While numerous risk loci disease-associated methylation variants have been identified, their functional impact and contribution to disease risk remain largely unclear. This study addresses a fundamental yet underexplored question: how do non-coding allele-specific methylation (ASM) sites influence disease risk via gene regulation? We employed the Mendelian randomization (MR) method to integrate ASM data from monozygotic twins discordant for psychiatric disorders with brain eQTL and GWAS summary statistics to identify potential risk genes. The regulatory of the rs2280906 locus was investigated using dual-luciferase reporter assays, gene expression quantification, gene editing, methylation editing, and electrophoretic mobility shift assays. We used MR to prioritize these ASM locus associated with schizophrenia risk and demonstrated that the affected genes are enriched in energy metabolism pathways-suggesting that targeting energy dysregulation may represent a promising therapeutic avenue. We further elucidated the allele-specific, methylation-dependent mechanism by which ASM site rs2280906 regulates risk gene MYOM2. In healthy individuals, hypomethylation of the reference C allele permits MYOM2 expression. In contrast, affected individuals exhibit hypermethylation of this allele, leading to biallelic methylation, increased recruitment of repressive transcription factors, and MYOM2 downregulation. Our study uncovers new risk genes regulated by ASM and provide mechanistic insight into the rs2280906-MYOM2 axis in schizophrenia. Our work advances understanding of how epigenetic regulation contributes to disease susceptibility and inter-individual variability, and offers new avenues for the identification of causal variants and therapeutic targets.