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, 18 185 total CNVs greater than 50 kilobases (10 517 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.

中文翻译：

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与费城神经发育队列青少年的认知、精神病理学和大脑结构相关的拷贝数变异风险评分。

重要性 精神病学和认知表型与一系列特定的、罕见的拷贝数变异 (CNV) 相关。此外，智商与 CNV 风险评分密切相关，该评分对整个基因组中 CNV 的预测风险进行建模。但 CNV 风险评分对于精神表型的实用性却很少被研究。目的 确定 CNV 风险评分、多基因评分 (PGS) 索引的常见遗传变异以及环境因素如何与社区样本中的认知和精神病理学相关。设计、设置和参与者 费城神经发育队列是一项基于社区的研究，研究遗传学、精神病理学、神经认知和神经影像学。参与者是通过费城儿童医院儿科网络招募的。健康状况稳定且英语流利的参与者于2009年11月5日至2011年12月30日期间接受了基因型和表型表征。数据于2021年1月1日至7月30日进行分析。 暴露 该研究检查了(1)从模型得出的CNV风险评分负担、预测的不耐受性和基因剂量敏感性；(2) 来自与发育结果相关的全基因组关联研究的 PGS；(3) 环境因素，包括创伤暴露和社区社会经济状况。主要成果和措施该研究检查了（1）神经认知，使用宾夕法尼亚大学计算机化神经认知电池；(2) 精神病理学，根据学龄儿童情感障碍和精神分裂症时间表进行结构化访谈；(3) 脑容量，磁共振成像。结果 参与者包括 9498 名 8 至 21 岁青少年；4906 名 (51.7%) 为女性，平均 (SD) 年龄为 14.2 (3.7) 岁。经过质量控制，在 Illumina 芯片上进行基因分型的 7101 名不相关参与者中，鉴定出 18185 个总 CNV 大于 50kb（10517 个缺失和 7668 个重复）。在这些参与者中，CNV 风险评分升高与认知测试的总体准确性较低相关（标准化 β = 0.12；95% CI，0.10-0.14；P = 7.41 × 10-26）；一系列认知子领域的准确性较低；整体精神病理学增加；精神病谱系症状增加；与脑容量正常发育模型的偏差更大。当 CNV 风险评分与 PGS 和环境因素相结合时，发育结果的统计模型得到显着改善。结论和相关性 在这项研究中，CNV 风险评分升高与较低的认知能力、较高的精神病理学（包括精神病谱症状）以及与大脑发育的规范磁共振成像模型的较大偏差相关。总之，这些结果代表了综合罕见遗传、常见遗传和环境因素以了解青少年临床相关结果的一步。