遺伝的変異と神経発達障害

タイトル: The copy number variant architecture of psychopathology and cognitive development in the ABCD study

概要: ImportanceChildhood is a crucial developmental phase for mental health and cognitive function, both of which are commonly affected in patients with psychiatric disorders. This neurodevelopmental trajectory is shaped by a complex interplay of genetic and environmental factors. While common genetic variants account for a large proportion of inherited genetic risk, rare genetic variations, particularly copy number variants (CNVs), play a significant role in the genetic architecture of neurodevelopmental disorders. Despite their importance, the relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. ObjectiveInvestigating CNV associations with dimensions of child psychopathology and cognitive functions. Design, Setting, and ParticipantsABCD(R) study focuses on a cohort of over 11,875 youth aged 9 to 10, recruited from 21 sites in the US, aiming to investigate the role of various factors, including brain, environment, and genetic factors, in the etiology of mental and physical health from middle childhood through early adulthood. Data analysis occurred from April 2023 to April 2024. Main Outcomes and MeasuresIn this study, we utilized PennCNV and QuantiSNP algorithms to identify duplications and deletions larger than 50Kb across a cohort of 11,088 individuals from the Adolescent Brain Cognitive Development(R) study. CNVs meeting quality control standards were subjected to a genome-wide association scan to identify regions associated with quantitative measures of broad psychiatric symptom domains and cognitive outcomes. Additionally, a CNV risk score, reflecting the aggregated burden of genetic intolerance to inactivation and dosage sensitivity, was calculated to assess its impact on variability in overall and dimensional child psychiatric and cognitive phenotypes. ResultsIn a final sample of 8,564 individuals (mean age=9.9 years, 4,532 males) passing quality control, we identified 4,111 individuals carrying 5,760 autosomal CNVs. Our results revealed significant associations between specific CNVs and our phenotypes of interest, psychopathology and cognitive function. For instance, a duplication at 10q26.3 was associated with overall psychopathology, and somatic complaints in particular. Additionally, deletions at 1q12.1, along with duplications at 14q11.2 and 10q26.3, were linked to overall cognitive function, with particular contributions from fluid intelligence (14q11.2), working memory (10q26.3), and reading ability (14q11.2). Moreover, individuals carrying CNVs previously associated with neurodevelopmental disorders exhibited greater impairment in social functioning and cognitive performance across multiple domains, in particular working memory. Notably, a higher deletion CNV risk score was significantly correlated with increased overall psychopathology (especially in dimensions of social functioning, thought disorder, and attention) as well as cognitive impairment across various domains. Conclusions and RelevanceIn summary, our findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology. Key PointsO_ST_ABSQuestionC_ST_ABSAre copy number variants (CNVs) contributing to individualized variability in psychopathology outcomes and cognitive functions in children? FindingsBoth regional CNVs at 1q12.1, 10q26.3 and 14q11.2 and global CNV burden accounted for the variance in dimensions of psychopathology, particularly for attention and social problems, as well as cognitive performance, especially for working memory and reading ability. MeaningOur findings suggest that, in addition to common genetic variants, gene dosage changes confer genetic susceptibility to child psychopathology and cognitive development.