Causal evidence linking injury-associated DNA methylation to the risk of developing depression or post-traumatic stress disorder.

Depression and post-traumatic stress disorder (PTSD) are common psychiatric disorders following physical trauma. However, genetic evidence between these disorders is lacking. DNA methylation (DNAm) is implicated in the response to traumatic events and has been proposed as a promising therapeutic target. This study aimed to investigate the causal evidence of injury-associated DNAm and the subsequent onset of depression or PTSD. We performed co-methylation analysis of the whole-genome bisulfite sequencing (WGBS) data from physical trauma patients who developed subsequent depression or PTSD. DNA methylation quantitative trait loci (mQTL) from the GoDMC database, expression quantitative trait loci (eQTL) from the eQTLGen consortium (phase Ⅰ), and genome-wide association (GWAS) summary statistics from the FinnGen consortium were used for causal inference using the mendelian randomization (MR) framework. Our results showed significant causal genetic evidence for injury-associated DNAm changes at cg24526596 (DLGAP2), cg00157656 (ERICH1), cg12317217 (PCDHA2), and cg12661624 (PTPRN2) on depression onset. However, no strong causal evidence was found for injury-associated DNAm and PTSD. The present study provided genetic evidence supporting the causal role of DNAm in the onset of depression or PTSD after injury and identified DLGAP2, ERICH1, PCDHA2, and PTPRN2 as the candidate genes worthy of further exploratory investigation.