PSIGE-understanding-Psychosis-Susceptibility-through-InterGenerational-and-Neurodevelopmental-risk

Relevance

Early detection of impairing psychosis vulnerability is one of the most pressing challenges in youth mental health services and research. Psychosis risk often manifests early in life, yet it is seldom recognized as such—particularly because prodromal difficulties in attention, concentration, and social interaction are non-specific indicators of early-stage psychosis. Current prevention efforts fall short: they focus only on help-seeking high-risk individuals, target the individual rather than the system, and examine isolated risk factors. The critical question remains: for whom, how, and when do these early precursors actually signal an increased risk of developing psychosis?

Goals

This project aims to develop and validate developmentally sensitive prediction models for psychosis vulnerability. Using novel analytical approaches, I will investigate how the intergenerational transmission of psychosis risk from parents to offspring is shaped by gene-environment (GxE) interactions. Furthermore, taking a life-course perspective, I will explore the timing of risk and protective factors. In essence, the goal is to understand not just GxE, but gene × environment × development (GxExD), in order to identify sensitive risk windows. These will then be incorporated into predictive models validated in familial high-risk cohorts of children with parents exhibiting psychosis vulnerability.

Impact

This research will contribute to the identification of “windows of opportunity” in clinical care, allowing for more effective early detection and tailored support for youth at elevated risk of psychosis. By actively collaborating with young people, patient organizations, and caregivers, we will incorporate diverse stakeholder perspectives. Crucially, by focusing on resilience—not solely on risk—this project will offer a more hopeful and constructive narrative for young individuals. Altogether, the outcomes of this research will drive critical innovation in the early detection and prevention of psychosis vulnerability.

Study design

In this project, we will use rich longitudinal data from the population-based Generation R Study with the addition of longitudinal high-risk offspring studies, a unique and valuable combination. Novel genetic trio analyses will be applied by including DNA from fathers, mothers and children. This genetic trio method will offer the opportunity to disentangle genetic and environmental routes of transmission of risk and resilience. To study this, we will include data on polygenic scores for psychosis and neurodevelopmental spectrum disorders, as well as longitudinal assessments of early life stress domains (e.g. life events, contextual risk, parental risk, and direct victimization).

Innovation

This project is novel by 1) applying new parent-offspring GxE interplay designs allowing for the analyses of not only individual but also familial factors; 2) creating developmentally sensitive prediction models to identify ‘windows of opportunity’ and resiliency; and 3) bridging a gap between general population and high-risk designs.

This project is funded by ZonMw.

Collaboration within of Erasmus MC

• Department of Child and Adolescent Psychiatry/Psychology

• Department of Epidemiology

Collaboration outside of Erasmus MC

• Erasmus University Rotterdam (EUR), Department of Psychology, Education and Child Studies.

• University College London (UCL), Department of Clinical, Educational & Health Psychology, division of Psychology & Language Sciences.

• Nationale Jeugdraad (NJR)

• Ypsilon

• Anoiksis

• A Prospective Cohort Study on the Intergenerational Transmission of Childhood Adversity and Subsequent Risk of Psychotic Experiences in Adolescence.
  Bolhuis K, Steenkamp LR, Tiemeier H, Blanken L, Pingault JB, Cecil CAM, El Marroun H. 2023. . Schizophr Bull. 2023 May 3;49(3):799-808.

• Schizophrenia polygenic risk is associated with child mental health problems through early childhood adversity: evidence for a gene-environment correlation.
  Bolhuis K, Steenkamp LR, Blanken LME, Neumann A, Jansen PR, Hillegers MHJ, Cecil CAM, Tiemeier H, Kushner SA. 2022.  Eur Child Adolesc Psychiatry. 2022  Mar;31(3):529-539.

• Koen Bolhuis, MD PhD, child and adolescent psychiatrist and assistant professor

• Charlotte Cecil, PhD, associate professor

• Neeltje van Haren, PhD, full professor

• Manon Hillegers, MD PhD, child and adolescent psychiatrist and departmental head

• Pauline Jansen, PhD, full professor

• Esther Mesman, PhD, healthcare psychologist and assistant professor

• Jean-Baptiste Pingault, PhD, full professor