CHOP Study Aims to Reveal How Genetics, Environment Contribute to Psychiatric and Cognitive Outcomes

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Aaron Alexander Bloch headshot Researchers at Children’s Hospital of Philadelphia (CHOP) have integrated environmental, genetic, and imaging data to better understand which factors might be clinically relevant when it comes to psychiatric and cognitive outcomes. Publishing their findings in a recent study in JAMA Psychiatry, the researchers found that elevated risk from rare genetic variations, known as copy number variants (CNVs), was associated with lower cognitive ability, higher psychopathology, and greater deviations from typical brain development.

CNVs are deletions or duplications of segments of the human genome and have been identified as contributors to complex diseases, including schizophrenia and autism, as well as intellectual disabilities. However, most clinically relevant CNVs are very rare, and two patients with the same CNVs will not necessarily experience the same symptoms or disease course. Thus, researchers have recognized the importance of examining other risk factors, such as common genetic variation, environmental factors, and the cumulative effect of multiple CNVs.

To better understand the influence of multiple factors on mental and cognitive outcomes, the researchers analyzed 9,498 patients between the ages of 8 and 21 who were part of the community-based Philadelphia Neurodevelopmental Cohort. The study examined patients’ CNV risk scores, which predict the risk of a particular CNV; polygenic risk scores (PGSs), which estimate an individual's genetic liability to a trait or disease based on genome-wide association studies (GWAS); and environmental factors, including trauma exposure and neighborhood socioeconomic status. Additionally, the researchers analyzed neurocognition, psychopathology, and brain volume with magnetic resonance imaging (MRI).

The researchers found that elevated CNV risk scores were associated with lower overall accuracy on cognitive tests; lower accuracy across a range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from typical brain volume. When CNV risk scores were combined with PGSs and environmental factors, the researchers found that their statistical models could more reliably predict the significance of CNVs. Elevated CNV risk scores were associated with greater deviations from typical brain development measured via brain growth charts also created by the team at CHOP and co-authors in a recent study published in Nature.

“Our study represents a step toward synthesizing rare genetic, common genetic, and environmental factors to improve our understanding of their associations with clinically relevant outcomes in youth,” said Aaron Alexander-Bloch, MD, PhD, Director of the Brain-Gene-Development Laboratory at Children’s Hospital of Philadelphia and first author of the study. “Future studies should continue to investigate the possibility of convergent molecular or functional pathways mediating the association between CNV risk scores and developmental outcomes and potentially optimizing risk scores for specific psychiatric conditions.”

Contact: The Children’s Hospital of Philadelphia,