For a study, researchers sought to determine how copy number variants (CNV) risk scores, common genetic variation quantified by polygenic scores (PGSs), and environmental variables interact to influence cognition and psychopathology in a community population.

The Philadelphia Neurodevelopmental Cohort is a community-based research project that looks at genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the pediatric network at Children’s Hospital of Philadelphia. From November 5, 2009, through December 30, 2011, participants with stable health and English fluency received genotypic and phenotypic characterization. The data were examined from January 1 to July 30, 2021.

The Investigators looked at copy number variants (CNVs) risk scores derived from the burden, anticipated intolerance, gene dosage sensitivity models, PGSs from genomewide association studies associated with developmental outcomes, and environmental variables such as trauma exposure and neighborhood socioeconomic status. The Penn Computerized Neurocognitive Battery was used to assess neurocognition; structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children were used to assess psychopathology, and magnetic resonance imaging was used to assess brain volume.

There were 9,498 juveniles aged 8 to 21 years in the study; 4,906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 7,101 unrelated subjects genotyped on Illumina arrays had 18,185 total CNVs bigger than 50 kilobases (10,517 deletions and 7,668 duplications). Elevated CNV risk scores were associated with lower overall accuracy on cognitive tests (standardized β=0.12; 95% CI, 0.10-0.14; P=7.41×10-26); lower accuracy across a variety of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume in these participants. When CNV risk ratings were integrated with PGSs and environmental variables, statistical models of developmental outcomes improved dramatically.

Elevated CNV risk scores were linked to worse cognitive ability, higher psychopathology, psychosis-spectrum symptoms, and more departures from normative magnetic resonance imaging models of brain development in this investigation. The findings offered an important step toward understanding clinically relevant outcomes in kids by combining uncommon genetic, common genetic, and environmental variables.