Differential interactions between gene expressions and stressors across the lifespan in major depressive disorder

Background: Both genetic predispositions and exposures to stressors have collectively contributed to the development of major depressive disorder (MDD). To deep dive into their roles in MDD, our study aimed to examine which susceptible gene expression interacts with various dimensions of stressors in the MDD risk among a large population cohort. Methods: Data analyzed were from a longitudinal community-based cohort from Southwest Montreal, Canada (N = 1083). Latent profile models were used to identify distinct patterns of stressors for the study cohort. A transcriptome-wide association study (TWAS) method was performed to examine the interactive effects of three dimensions of stressors (threat, deprivation, and cumulative lifetime stress) and gene expression on the MDD risk in a total of 48 tissues from GTEx. Additional analyses were also conducted to further explore and specify these associations including colocalization, and fine-mapping analyses, in addition to enrichment analysis investigations based on TWAS. Results: We identified 3321 genes linked to MDD at the nominal p-value <0.05 and found that different patterns of stressors can amplify the genetic susceptibility to MDD. We also observed specific genes and pathways that interacted with deprivation and cumulative lifetime stressors, particularly in specific brain tissues including basal ganglia, prefrontal cortex, brain amygdala, brain cerebellum, brain cortex, and the whole blood. Colocalization analysis also identified these genes as having a high probability of sharing MDD causal variants. Limitations: The study cohort was composed exclusively of individuals of Caucasians, which restricts the generalizability of the findings to other ethnic population groups. Conclusions: The findings of the study unveiled significant interactions between potential tissue-specific gene expression × stressors in the MDD risk and shed light on the intricate etiological attributes of gene expression and specific stressors across the lifespan in MDD. These genetic and environmental attributes in MDD corroborate the vulnerability-stress theory and direct future stress research to have a closer examination of genetic predisposition and potential involvements of omics studies to specify the intricate relationships between genes and stressful environments.