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[Preprint]. 2024 May 15:2024.05.14.24307376.
doi: 10.1101/2024.05.14.24307376.

The copy number variant architecture of psychopathology and cognitive development in the ABCD® study

Zhiqiang Sha  1   2   3 , Kevin Y Sun  1   2   3 , Benjamin Jung  4 , Ran Barzilay  1   2   3 , Tyler M Moore  1 , Laura Almasy  3   5   6 , Jennifer K Forsyth  7 , Smrithi Prem  8   9 , Michael J Gandal  1   3   6 , Jakob Seidlitz  1   2   3 , Joseph T Glessner  10 , Aaron F Alexander-Bloch  1   2   3
Affiliations

The copy number variant architecture of psychopathology and cognitive development in the ABCD® study

Zhiqiang Sha et al. medRxiv. .

Abstract

Importance: Childhood 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.

Objective: Investigating CNV associations with dimensions of child psychopathology and cognitive functions.

Design setting and participants: ABCD® 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 measures: In 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® 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.

Results: In 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 relevance: In summary, our findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.

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Conflict of interest statement

Conflict of interests AFA-B receives consulting income from Octave Bioscience. AFA-B and JS hold equity in and serve on the board of Centile Bioscience.

Figures

Figure 1.
Figure 1.. The landscape of the CNV calls in the ABCD® study.
After conservative quality control, we report 5760 CNVs among 8564 individuals from the ABCD® study. The figure illustrates the chromosomal distribution of all deletions and duplications called in the ABCD® study, in which blue represents deletions, and red represents duplications.
Figure 2.
Figure 2.. Genome-wide CNVRs associations with overall psychopathology and cognitive function.
(A) Genome-wide CNVR association with overall psychopathology. Manhattan plot illustrates significant CNVR associations with the overall psychopathology measure at Bonferroni-corrected p<2.5×10−4 (i.e., 5×10−4/2), the recommended threshold for genome-wide significance in the ParseCNV2 platform. Blue lines under the Manhattan plot represent the 16 duplications contributing to the significant CNVR association. The black line and the genes below them indicate the genomic position of genes encompassed by the CNVR significantly associated with psychopathology. The Manhattan plot at the bottom illustrates the GWAS association of psychiatric disorders with common genetic variants (i.e., SNPs) within the identified CNVR, as reported by Romero et al. (B) Genome-wide CNVR association with global cognitive function. Three CNVRs were found significantly associated with the overall cognitive function at Bonferroni-corrected p<2.5×10−4 (i.e., 5×10−4/2). Blue lines under the Manhattan plot represent the CNVs that contribute to each significant CNVR association. The black lines and the genes below them indicate the genomic position of genes encompassed by the CNVR significantly associated with global cognitive function. The Manhattan plot at the bottom illustrates GWAS SNP associations with general intelligence within each CNVR, as reported by Savage et al..
Figure 3.
Figure 3.. Genome-wide CNVRs associations with dimensions of psychopathology and cognitive function.
A) Across 8 dimensions of psychopathology, we found duplication of 14:20247780–20423950 at 14q11.2 was significantly associated with attention problems at Bonferroni-corrected p<1×10−4 (i.e., 5×10−4 divided by 5, which is the effective number of tests across 8 dimensions of psychopathology). B-D) Across 8 domains of cognitive functions, we found associations between CNVRs and fluid intelligence (B), working memory (C) and reading ability (D) after multiple testing correction (p<5×10−4 divided by 6, which is the effective number of tests across 8 dimensions of cognitive function). Dashed line indicates the threshold of genome-wide significance for each phenotype.
Figure 4.
Figure 4.. Associations of psychopathology and cognitive function with individuals carrying known pathogenic recurrent CNVs associated with neurodevelopmental disorders.
(A) Association of overall and dimensional psychopathology with neurodevelopmental CNVs. Individuals with neurodevelopmental CNVs had significantly elevated psychopathology in the social domain at FDR-corrected p<0.05. (B) Association of global and dimensional cognitive function with neurodevelopmental CNVs. Individuals with neurodevelopmental CNVs had lower cognitive performance across domains including fluid intelligence, attention, working memory, flexible thinking, reading ability and processing speed (pFDR<0.05). Points in the dot plots indicate the value of a given predictor variable’s standardized effect size and error bars indicate 95%CIs for models of cognition and psychopathology.
Figure 5.
Figure 5.. Associations of psychopathology and cognitive function with CNV risk scores.
To determine the cumulative effect of CNVs on psychopathology and cognition, we used regression models to test associations with global and dimensional cognitive functions for each of 5 CNV risk scores across 8564 individuals, including the size of CNV (A), the number of genes overlapping with the CNV (B), the probability of loss intolerance (C), the inverse of the loss of function observed/expected upper bound fraction (D), dosage sensitivity (E). Similarly, we also tested associations with global and dimensions of psychopathology for each of the 5 CNV risk scores (F-J). Points in the dot plots indicate the value of a given predictor variable’s effect size and error bars indicate 95%CIs for models of cognition and psychopathology.
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