The effect of polygenic risk score and childhood adversity on transdiagnostic symptom dimensions at first-episode psychosis: evidence for an affective pathway to psychosis

Abstract

Childhood adversity is associated with various clinical dimensions in psychosis; however, how genetic vulnerability shapes the adversity-associated psychopathological signature is yet to be studied. We studied data of 583 First Episode Psychosis (FEP) cases from the EU-GEI FEP case-control study, including Polygenic risk scores for major depressive disorder (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS); childhood adversity measured with the total score of the Childhood Trauma Questionnaire (CTQ); and positive, negative, depressive and manic psychopathological domains from a factor model of transdiagnostic dimensions. Genes and environment interactions were explored as a departure from a multiplicative effect of PRSs and total CTQ on each dimension. Analyses were adjusted for age, sex, 10 PCA, site of recruitment and for medication. A childhood adversity and PRS multiplicative interaction was observed between A) the CTQ and MDD-PRS on the predominance of positive (β = 0.42, 95% CI = [0.155, 0.682], p = 0.004); and depressive (β = 0.33, 95% CI = [0.071, 0.591], p = 0.013) dimensions; B) between the CTQ and BD-PRS on the positive dimension (β = 0.45, 95% CI = [0.106, 0.798], p = 0.010), and C) with the CTQ and SZ-PRS on the positive dimension (β = -0.34, 95% CI = [-0.660, -0.015], p = 0.040). Bonferroni corrected p-value of significance was set at 0.0125. In conclusion, despite being underpowered, this study suggests that genetic liability for MDD and BD may have a moderating effect on the sensibility of childhood adversity on depressive and positive psychotic dimensions. This supports the hypothesis of an affective pathway to psychosis in those exposed to childhood adversity.

Fig. 1. Multiplicative interaction effects of childhood adversity and polygenic risk scores on psychopathological dimensions.

a Positive dimension, childhood adversity & PRS (MDD, BD, SZ) interactions. b Manic dimension childhood adversity & PRS (MDD, BD, SZ) interactions. c Depressive dimension, childhood adversity & (MDD, BD, SZ) interactions. d Negative dimension, childhood adversity & PRS (MDD, BD, SZ) interactions. This figure illustrates the magnitude of the multiplicative interaction effect of PRS of depression (MDD-PRS), bipolar disorder (BD-PRS) and schizophrenia (SZ-PRS) with adversity (measured with the Childhood Trauma Questionnaire total score). An interaction effect into the positive direction can be interpreted as an increased sensibility of adversity exposure on a dimension, moderated by genetic vulnerability.