Summary: Researchers used a broad, data-driven genetic screening approach to map links between inherited risk for psychiatric conditions and a wide range of behaviors, symptoms and environments in young people. The study found associations between polygenic risk scores and potentially modifiable factors such as screen time and caffeinated beverage consumption, offering leads for early prevention even though causality cannot yet be established.
While the findings do not prove cause and effect, they point to actionable areas for further study and early intervention during adolescence. The work also highlights the need for more diverse genomic datasets to increase the generalizability of results across populations.
Key Facts:
- Phenome-wide screening connects genetic risk for psychiatric disorders to many behavioral and environmental traits.
- Associations include screen time, energy drink consumption and exposure to stressful life events.
- The study underscores the importance of expanding genomic research beyond European-ancestry reference populations.
Source: WUSTL
Researchers at Washington University in St. Louis used a broad, hypothesis-free strategy to investigate how genetic predisposition to psychiatric disorders relates to the wide array of behaviors and experiences that shape youth development.
Using this exploratory, “big-net” approach, the team identified numerous associations between genetic liability for mental health disorders and adolescent traits—ranging from sleep and attention problems to lifestyle behaviors like screen time and caffeine intake. The findings, published in Nature Mental Health, do not establish causation but provide important directions for follow-up work and preventive strategies.
“We’re casting a wide net to capture as many relevant traits as possible,” said Nicole Karcher, assistant professor of psychiatry at WashU Medicine. “The next steps are to examine which of these associations represent meaningful, modifiable targets for reducing risk.”
An innovative phenome-wide strategy
Most genomic-behavior research relies on genome-wide association studies (GWAS), which search for individual genetic variants linked to a single trait or disorder. Because many psychiatric conditions share genetic overlap, findings from a GWAS focused on one diagnosis can reflect broader, cross-disorder genetic influences.
To capture these cross-disorder links in a comprehensive way, the team performed a phenome-wide association study (PheWAS) that inverts the GWAS approach. Instead of starting with a phenotype and searching for genes, they began with genetic risk measures—polygenic risk scores (PRS) derived from prior GWAS—and tested their associations across hundreds to thousands of measured traits.
The researchers analyzed roughly 1,300–1,700 phenotypes drawn from the Adolescent Brain Cognitive Development (ABCD) Study. These phenotypes included behavioral symptoms, environmental factors, health indicators and intermediate measures such as brain structure. “We wanted a data-driven, agnostic view of how genetic liability might show up across many domains,” said lead author Sarah Paul.
The goal was to identify potential early, modifiable signals that emerge before clinical onset of psychiatric disorders and that could inform prevention and early-intervention efforts.
Major results
From 11 published GWAS, the team constructed four broad polygenic scores representing genetic liability for: neurodevelopmental disorders, internalizing disorders, compulsive disorders and psychotic disorders. Key associations included:
- Neurodevelopmental PRS (driven largely by ADHD and autism, and also reflecting depressive and alcohol-related risk) associated with about 190 phenotypes. These included attention and impulsivity problems, total screen time, sleep disturbances and psychotic-like experiences, as well as environmental indicators such as neighborhood crime rates and lower parental monitoring.
- Internalizing PRS (including depression, anxiety and PTSD) associated with roughly 120 phenotypes, such as depressive symptoms, exposure to stressful life events, psychotic-like experiences and screen time.
- Psychotic PRS (schizophrenia and bipolar disorder) showed fewer associations, with links observed to lower school involvement and greater consumption of energy drinks.
The authors emphasize these are correlations. For example, the link between psychotic liability and energy drink consumption does not mean caffeinated drinks cause psychosis; shared genetic factors may influence both traits. Nonetheless, such correlations highlight behaviors that could be examined as early intervention targets.
Karcher notes that the PheWAS is valuable for revealing clusters of associations that might not be discovered with narrower approaches—providing a “20,000-foot view” of genetic influences on adolescent behavior and risk.
Longitudinal follow-up of the ABCD cohort into adolescence and early adulthood will help determine how these genetic associations evolve over time and whether early behaviors predict later psychopathology.
“Tracking these youth as they mature will clarify whether links between genetic risk and traits like screen time, sleep and symptoms strengthen, weaken or change direction,” Paul said.
Overall, this study demonstrates how PheWAS methods can surface potential prevention targets—behaviors and exposures that are measurable in childhood and may be amenable to intervention before full-blown psychiatric disorders develop.
A major limitation is the limited diversity of available GWAS: most reference data come from populations of European ancestry, so the present PheWAS was restricted to ABCD participants genetically similar to those reference populations. Expanding GWAS and PRS methods to include more diverse populations will be critical for ensuring broader applicability of these findings.
Funding: Data for this study came from the Adolescent Brain Cognitive Development (ABCD) Study, supported by multiple NIH awards and federal partners. This project was supported by R01 DA054750. Individual authors received NIH and NSF support as detailed in the original publication.
About this genetics and mental health research news
Author: Leah Shaffer
Source: WUSTL
Contact: Leah Shaffer – WUSTL
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“A phenome-wide association study of cross-disorder genetic liability in youth genetically similar to individuals from European reference populations” by Nicole Karcher et al. Nature Mental Health
Abstract
A phenome-wide association study of cross-disorder genetic liability in youth genetically similar to individuals from European reference populations
Using hypothesis-free methods to probe connections between genetic risk for broad psychopathology and adolescent phenotypes can reveal etiologic signals. The authors conducted an exploratory PheWAS of polygenic risk scores representing compulsive, psychotic, neurodevelopmental and internalizing liability in youth most genetically similar to European reference populations (n = 5,556; ages 9–13) from the ABCD Study, analyzing 1,271–1,697 phenotypes across baseline and 2-year follow-up assessments.
Neurodevelopmental and internalizing PRS showed significant associations across multiple domains (neurodevelopmental: 190 and 214 phenotypes at baseline and follow-up; internalizing: 124 and 183 phenotypes), whereas compulsive and psychotic PRS had far fewer significant links after multiple-test correction. Some PRS were also associated with brain-structure metrics, though evidence was limited that brain structure served as a consistent indirect path from PRS to later outcomes.
Overall, genetic variation influencing risk for psychopathology appears early and broadly in behavior, symptoms and related risk factors during middle childhood and early adolescence.