Genome-wide identification of differentially methylated regions in prefrontal cortex of suicide completers in an Indian ancestral admixture population

Abstract

Abstract Objectives Suicide is a complex phenotype influenced by genetic, environmental, and psychosocial determinants. Epigenetic mechanisms, particularly DNA methylation, play a critical role in mediating the long-term effects of environmental stressors on gene expression within the brain, potentially contributing to suicide vulnerability. India represents the largest proportion of global suicide deaths, yet the majority of suicide epigenetics research has focused on individuals of Western admixture. Methods Differential methylation analysis using MeDIP-NGS on postmortem prefrontal cortex (Brodmann area 9/10; n=25 suicide completers/25 non-suicidal controls, Indian population) was performed. Results We identified 734 hypermethylated and 6,533 hypomethylated regions at suggestive p<0.0005 and (FC>|1|). Functional annotation revealed that hypermethylated genes were nominally enriched in pathways related to neurotransmitter signaling, synaptic transmission, and learning and cognition, whereas hypomethylated genes were related to neurodevelopment, neuronal connectivity, and morphogenesis. Transcription start site (TSS) mapping showed observed methylation patterns in promoter region (hypermethylation 14.29%, hypomethylation 29.03%) and first intron regions (18.78% vs 5.78%). Conclusion This exploratory methylome study observed differential methylation patterns across protein-coding genes, pseudogenes, and associated biological pathways in the prefrontal cortex of suicide completers. This discovery-level evidence forms a framework for future validation of candidate epigenetic markers and biological pathways in larger and more diverse populations.