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Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study.

Chawner, Samuel, Owen, Michael J., Holmans, Peter, Raymond, Lucy, Skuse, David, Hall, Jeremy and van den Bree, Marianne 2019. Genotype-phenotype relationships in children with copy number variants associated with high neuropsychiatric risk: Findings from the Intellectual Disability & Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study. bioRxiv 10.1101/535708

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Abstract

Background: A variety of copy number variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Different ND-CNVs could lead to distinct and specific patterns of cognitive and behavioural outcomes, but supporting evidence is currently lacking. Methods: 258 children with ND-CNVs (13 CNVs across 9 loci) were systematically assessed for psychiatric disorders as well as broader traits of neurodevelopmental, cognitive and psychopathological origin. A comparison was made with 106 non-carrier control siblings, in order to test the hypothesis that phenotypes would differ by genotype, both quantitatively, in terms of severity, and qualitatively in the pattern of associated impairments. Outcomes: 79.8% of ND-CNVs carriers met criteria for one or more psychiatric disorders (OR=13.8 compared to controls): the risk of ADHD (OR=6.9), ODD (OR=3.6), anxiety disorders (OR=2.9), and ASD traits (OR=44.1) was particularly high. ND-CNVs carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits relative to controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. In general, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, however the specific genotype accounted for a low proportion of variance in outcome (5-20% depending on trait). Interpretation: The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Our findings suggest that genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits, and provides important implications for research into genotype-phenotype relationships within psychiatry.

Item Type: Article
Date Type: Published Online
Status: Unpublished
Schools: Medicine
Publisher: Cold Spring Harbor Laboratory
Date of First Compliant Deposit: 7 February 2019
Last Modified: 25 Jul 2019 09:19
URI: http://orca.cf.ac.uk/id/eprint/119295

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