A genetic study of immunity in depression and interactions with childhood maltreatment

Genetic and environmental factors contribute to depression. Among the latter, early life adversity and immune dysregulation have been consistently linked with depression. Childhood maltreatment (CM) is believed to induce immune dysregulation later in life. However, it is not known how CM might interact with genetic immune factors to contribute to the occurrence of depression. We investigated how genetic variability in 2370 genes from 20 immune pathways associates with a broadly-defined lifetime depression phenotype at gene- and pathway-level, and how this variability interacts with CM. Depression analysis was carried out in 13,309 individuals (1867 cases) from Generation Scotland (GS). CM interaction analysis was carried out in a subset of 749 individuals (99 cases) from GS and an independent sample of 509 individuals (96 cases) from the German BiDirect (BD) Study for which both genetic and CM data was available. Interactions with different types of CM were tested using the subscales of the childhood trauma questionnaire (CTQ). These results were meta-analyzed to obtain general gene-CM interactions. We found association of the GHR gene (false discovery rate -FDR- = 0.03, z = 4.2) and Reactome "RUNX1-regulated transcription of genes involved in myeloid cell differentiation pathway" (FDR = 0.016, beta = 1.2) with depression in GS. After meta-analysis, 56 immune gene-CM interactions were associated with depression (FDR < 0.05) in both GS and BD. These exert functions in hematopoiesis, pathogen recognition and stress responses, among others. Network analysis suggested macrophages as main expressing cell types. Our results underscore the involvement of hematopoietic alterations and immune gene-CM interactions in the development of depression.