Early life stress shapes the impact of inflammatory polygenic risk on depression and suicidality

Background

Early life stress (ELS) is a well-established risk factor for depression and suicidal behaviour, potentially acting through long-term dysregulation of inflammatory and neurobiological systems. Increasing evidence suggests that the relationship between chronic inflammatory or autoimmune disorders and depression is not solely reactive but may reflect shared genetic vulnerability. Moreover, depression itself is heterogeneous, and different symptom dimensions or clinical outcomes—such as depressive severity versus suicidal ideation—may show distinct biological associations. Understanding how genetic liability to inflammatory conditions interacts with ELS to influence these outcomes may help clarify mechanisms linking somatic and psychiatric disorders.

Aims

Our study investigated whether genetic predisposition to autoimmune and inflammatory diseases is associated with depression and suicidal ideation, and whether these effects are moderated by early life stress using polygenic risk scores (PRS).

Methods

To calculate PRS we used pre-existing GWAS summary statistics for five autoimmune and inflammatory diseases: systhemic lupus erythematosus (SLE), atrophic gastritis (AG), autoimmune thyroid disease (AT), asthma bronchiale (AB), and metabolic syndrome (MS) using LDpred2. The NewMood database provided the independent target sample. Current depression and current suicidal ideation was evaluated using Brief Symptom Inventory. Early life stress (ELS) was measured using the Childhood Trauma Questionnaire. Associations between PRS-s calculated for the inflammatory conditions and outcomes including depression and suicidal ideation, as well as PRS x ELS interactions were investigated using regression models.

Results

The main effect analyses showed that only MS-PRS had a significant effect on depression (β=0.5843, p=0.0212) while AB-PRS (β=0.0352, p=0.7170), AG-PRS (β=0.4741, p=0.5795), AT-PRS (β=0.4095, p=0.9763) and SLE-PRS (β=0.1765, p=0.0751) did not show significant effect. MS-PRS also showed significant effects on suicidal ideation scores (β=0.2577, p=0.0309) while AB-PRS (β=0.0076, p=0.8653), AG-PRS (β=0.3879, p=0.2907), AT-PRS (β=0.3120, p=0.9617) and SLE-PRS (β=0.0861, p=0.0649) did not show significant main effects. In contrast, interaction analyses revealed that ELS significantly moderated the effects of certain autoimmune / inflammatory PRS-s ont he studied outcomes. Specifically, AG-PRS (β=0.6506, p=0.0031) and SLE-PRS (β=0.0710, p=0.0040) showed significant interactions with ELS in predicting depression scores. Similarly, AG-PRS (β=0.2289, p=0.0125) and SLE-PRS (β=0.0368, p=0.0018) interacted with ELS to predict suicidal ideation. No significant interaction effects were observed for PRS-AB (β=0.0128, p=0.2751), PRS-AT (β=1.195, p=0.4545), or PRS-MS (β=0.0286, p=0.3408).

Discussion

Our findings suggest distinct pathways linking genetic liability to inflammatory / autoimmune conditions, early life stress, and affective outcomes. Genetic risk for metabolic syndrome appears to exert a direct association with depression and suicidal ideation, independent of ELS, whereas genetic predisposition to autoimmune disorders such as SLE and atrophic gastritis may confer risk primarily in the context of early environmental adversity. This pattern highlights the importance of considering both genetic and environmental factors in a complex approach, as well as distinguishing between different clinical outcomes within depression. The results support a model in which inflammatory and immunological processes contribute to depression and suicidality through multiple, partially independent mechanisms. Elucidating these pathways may improve risk stratification and inform more targeted prevention and intervention strategies, particularly for individuals exposed to early life stress.

References

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