Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles

Progress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context. Using self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education). MD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood. The observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.