Childhood immunomodulatory biomarkers and risk of depression and psychosis-spectrum outcomes at age 24: longitudinal evidence from the ALSPAC birth cohort

Background
Evidence from longitudinal studies demonstrates an association between pro-inflammatory markers and risk of psychiatric outcomes, however the role of immune regulators remain largely underexplored.
Hypothesis
We hypothesized that childhood immunomodulatory biomarkers are inversely associated with depression and psychosis-spectrum outcomes in adulthood.
Methods
We analysed data from 2,068 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma samples collected at age 9 were assayed for immunomodulatory biomarkers (IL10, sCD5, sCD6, LAP TGF-β1, OPG, PD-L1, TRAIL, and LIFR) using Olink Inflammatory Panel. Psychiatric outcomes at age 24 included moderate-to-severe depression, psychotic experiences and negative symptoms. Logistic regression models tested associations between cytokine levels and binary outcomes, while linear regression models were used for negative symptoms score. These models were adjusted for sex, BMI at age 9, ethnicity, and paternal social class. Exploratory analyses additionally tested interactions between immunomodulatory biomarkers and early life trauma (ages 0–5). False discovery rate (FDR) correction was applied using Benjamini-Hochberg procedure.
Results
In our sample, 260 participants (12.6%) had moderate-to-severe depression (N = 148) and/or psychotic experiences (N = 141) at age 24. Childhood CD5 was associated with lower odds of depression (adjustedOR = 0.75, 95% CI: 0.63–0.90, FDR = 0.008) and negative symptoms (aβ = -0.31, 95% CI −0.55 to −0.07, FDR = 0.048). Childhood CD6 was similarly associated with lower odds of depression (aOR = 0.79, 95% CI: 0.67–0.94, FDR = 0.032), fewer negative symptoms (aβ = –0.38, 95% CI: –0.62 to –0.14, FDR = 0.016), and a lower odds of psychotic experiences (aOR = 0.78, 95% CI: 0.65–0.93, FDR = 0.040). None of the other biomarkers showed longitudinal associations following confounding adjustment. There was no evidence that childhood immunoregulatory biomarkers modified effect of early life trauma on psychiatric outcomes.
Conclusions
Higher childhood CD5 and CD6 levels were associated with lower odds of depression and psychosis-spectrum outcomes in early adulthood, consistent with a role of early-life immune function, particularly immune regulation, in the aetiology of these conditions. However, effect-sizes were modest and further work is needed to clarify whether anti-inflammatory phenotypes are protective in developmental psychopathology.