Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene–environment correlation

Abstract

Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene–environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02–1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01–1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5–23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene–environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities.

Childhood maltreatment mediates the effect of the genetic background on psychosis risk in young adults

“…The current study extends the relationship between SZ-PRS and CM to early adulthood and finds evidence of a role as mediator of genetic risk for CM. Moreover, the proportion of the effect of SZ-PRS on PLE mediated by CM in our study is much higher compared to that for emotional and cognitive problems reported by Bolhuis et al [ 22 ]. These findings are consistent with a pleiotropic influence of schizophrenia genes.…”

“…From that perspective, the observation that CM is also associated with SZ-PRS in two independent, population-based, cohorts is very relevant. Previous research already reported a link between SZ-PRS and CM, with an indirect influence on emotional, attention, and thought problems in children [ 22 ]. The current study extends the relationship between SZ-PRS and CM to early adulthood and finds evidence of a role as mediator of genetic risk for CM.…”

“…Evidence that genetic risks are related to environmental exposures, thereby producing gene–environment correlations (rGE), are mounting [ 17 – 19 ]. Recent studies have identified genetic risks to CM and proposed causal relations between CM and severe mental health conditions, including schizophrenia [ 20 , 21 ] and a first study found that schizophrenia risk genes can predict poorer child mental health, through increased exposure to CM [ 22 ].…”

Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis

“… 43 Furthermore, a prospective birth cohort (Generation R) of 1901 participants found schizophrenia PRS to be associated with maternal reports of childhood adversity (OR = 1.08; 95% CI = 1.02, 1.15; P = .01) which the authors replicated in the ALSPAC cohort (OR = 1.02; 95% CI = 1.01, 1.03; P = .001). 44 Further analyses demonstrated that this association was driven by childhood adversities occurring before the age of 5 years (OR = 1.20; 95% CI = 1.05, 1.36; P < .01). A study of 5947 participants from a university student population (age 18–22) found that schizophrenia PRS predicted a report of previous trauma, although the study is limited by its retrospective nature and the lack of information on the timing of the trauma.…”

“… 46 Finally, 2 clinical studies 47 , 48 assessed the relationship between global childhood adversity and schizophrenia PRS in their control samples and both found positive associations, although only one was statistically significant. 44 These studies are discussed further in the “Clinical Studies” section.…”