TY - JOUR
T1 - Copy Number Variant Risk Scores Associated with Cognition, Psychopathology, and Brain Structure in Youths in the Philadelphia Neurodevelopmental Cohort
AU - Alexander-Bloch, Aaron
AU - Huguet, Guillaume
AU - Schultz, Laura M.
AU - Huffnagle, Nicholas
AU - Jacquemont, Sebastien
AU - Seidlitz, Jakob
AU - Saci, Zohra
AU - Moore, Tyler M.
AU - Bethlehem, Richard A.I.
AU - Mollon, Josephine
AU - Knowles, Emma K.
AU - Raznahan, Armin
AU - Merikangas, Alison
AU - Chaiyachati, Barbara H.
AU - Raman, Harshini
AU - Schmitt, J. Eric
AU - Barzilay, Ran
AU - Calkins, Monica E.
AU - Shinohara, Russel T.
AU - Satterthwaite, Theodore D.
AU - Gur, Ruben C.
AU - Glahn, David C.
AU - Almasy, Laura
AU - Gur, Raquel E.
AU - Hakonarson, Hakon
AU - Glessner, Joseph
N1 - Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/7
Y1 - 2022/7
N2 - Importance: Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined. Objective: To determine how CNV risk scores, common genetic variation indexed by polygenic scores (PGSs), and environmental factors combine to associate with cognition and psychopathology in a community sample. Design, Setting, and Participants: The Philadelphia Neurodevelopmental Cohort is a community-based study examining genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the Children's Hospital of Philadelphia pediatric network. Participants with stable health and fluency in English underwent genotypic and phenotypic characterization from November 5, 2009, through December 30, 2011. Data were analyzed from January 1 through July 30, 2021. Exposures: The study examined (1) CNV risk scores derived from models of burden, predicted intolerance, and gene dosage sensitivity; (2) PGSs from genomewide association studies related to developmental outcomes; and (3) environmental factors, including trauma exposure and neighborhood socioeconomic status. Main Outcomes and Measures: The study examined (1) neurocognition, with the Penn Computerized Neurocognitive Battery; (2) psychopathology, with structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children; and (3) brain volume, with magnetic resonance imaging. Results: Participants included 9498 youths aged 8 to 21 years; 4906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 18185 total CNVs greater than 50 kilobases (10517 deletions and 7668 duplications) were identified in 7101 unrelated participants genotyped on Illumina arrays. In these participants, 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 range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume. Statistical models of developmental outcomes were significantly improved when CNV risk scores were combined with PGSs and environmental factors. Conclusions and Relevance: In this study, elevated CNV risk scores were associated with lower cognitive ability, higher psychopathology including psychosis-spectrum symptoms, and greater deviations from normative magnetic resonance imaging models of brain development. Together, these results represent a step toward synthesizing rare genetic, common genetic, and environmental factors to understand clinically relevant outcomes in youth..
AB - Importance: Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined. Objective: To determine how CNV risk scores, common genetic variation indexed by polygenic scores (PGSs), and environmental factors combine to associate with cognition and psychopathology in a community sample. Design, Setting, and Participants: The Philadelphia Neurodevelopmental Cohort is a community-based study examining genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the Children's Hospital of Philadelphia pediatric network. Participants with stable health and fluency in English underwent genotypic and phenotypic characterization from November 5, 2009, through December 30, 2011. Data were analyzed from January 1 through July 30, 2021. Exposures: The study examined (1) CNV risk scores derived from models of burden, predicted intolerance, and gene dosage sensitivity; (2) PGSs from genomewide association studies related to developmental outcomes; and (3) environmental factors, including trauma exposure and neighborhood socioeconomic status. Main Outcomes and Measures: The study examined (1) neurocognition, with the Penn Computerized Neurocognitive Battery; (2) psychopathology, with structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children; and (3) brain volume, with magnetic resonance imaging. Results: Participants included 9498 youths aged 8 to 21 years; 4906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 18185 total CNVs greater than 50 kilobases (10517 deletions and 7668 duplications) were identified in 7101 unrelated participants genotyped on Illumina arrays. In these participants, 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 range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume. Statistical models of developmental outcomes were significantly improved when CNV risk scores were combined with PGSs and environmental factors. Conclusions and Relevance: In this study, elevated CNV risk scores were associated with lower cognitive ability, higher psychopathology including psychosis-spectrum symptoms, and greater deviations from normative magnetic resonance imaging models of brain development. Together, these results represent a step toward synthesizing rare genetic, common genetic, and environmental factors to understand clinically relevant outcomes in youth..
UR - http://www.scopus.com/inward/record.url?scp=85130522670&partnerID=8YFLogxK
U2 - 10.1001/jamapsychiatry.2022.1017
DO - 10.1001/jamapsychiatry.2022.1017
M3 - Article
AN - SCOPUS:85130522670
SN - 2168-622X
VL - 79
SP - 699
EP - 709
JO - JAMA Psychiatry
JF - JAMA Psychiatry
IS - 7
ER -