The Youth-GEMs project: genetic and environmental interactions underlying trajectories of youth mental health

Most mental disorders emerge before age 24, yet the mechanisms shaping youth mental health trajectories remain poorly understood. Here, we present the The Youth-GEMs project (“Gene Environment interactions in Mental health trajectorieS of Youth”). This multidisciplinary, multisite research project funded with a running period from 2022 – 2027 aims to i) advance the molecular and neurobiological understanding of the interplay between genetic, epigenetic, and environmental factors across development in driving or preventing the transition from mental health to mental illness in young people, and ii) provide youth and health professionals with evidence-based tools and instruments for robust assessment of mental ill-health and for prediction of mental health trajectories. To address these aims, the Youth-GEMs consortium unites the expertise of 18 complementary partners, including academic, clinical, industrial institutions, and youth mental health networks from across Europe and Australia. The Youth-GEMs project has an integrated, developmental framework that examines how genetic, epigenetic, and environmental factors dynamically interact to influence risk and resilience across adolescence and young adulthood. The project combines developmental (epi)genomic mapping of the human brain, genomic analyses of trans-syndromal phenotypes, exposome-wide environmental assessment, and Artificial Intelligence-based modelling to identify predictive and actionable markers of mental health trajectories of young people. By harmonizing multimodal data from existing population-based cohorts covering early postnatal development up to ages of 25 and by establishing the first international, trans-syndromal clinical cohort of help-seeking young people, Youth-GEMs is generating biologically informed polygenic and exposomic scores, cell-type–specific regulatory annotations, and interpretable machine-learning models. The clinical work package of the project has established a comprehensive transdiagnostic assessment battery for help-seeking young people and its ongoing longitudinal clinical cohort study of help-seeking young people is conducted at six sites across Europe (Spain, Finland, the Netherlands, Estonia, Croatia, and Serbia), and will integrate data from a comparable study conducted at three sites in Australia. This European clinical study makes use of a harmonized trans-syndromal clinical assessment protocol that is: 1) acceptable for clinicians and young people, 2) applicable across adolescence and young adulthood in clinical and non-clinical settings, 3) appropriate for trans-syndromal dimensional studies, 4) flexible, and 5) developmentally and cross-culturally appropriate. The protocol furthermore includes biological and digital phenotyping as well as a detailed follow-back assessment of clinical manifestations, environmental exposures, and pathways to care preceding study inclusion. The study protocol is registered at the International Clinical Trials Registry Platform, see https://www.isrctn.com/ISRCTN17131459. Prediction accuracy, usability, interpretability, and clinical impact of the clinical and digital phenotyping protocols and the corresponding prediction model will be established and the relative contribution of clinical, biological, environmental, and digital factors as predictors for mental health trajectories will be established. Continuous engagement with young people, clinicians, and stakeholders ensures that findings translate into tools for early detection, monitoring, and personalized intervention. Together, these efforts advance mechanistic understandings of youth mental health, improve prediction of emerging illness, and support the development of evidence-based, developmentally sensitive approaches to prevention and care.

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