Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Genotype-phenotype relationships in children with Copy Number Variants associated with high neuropsychiatric risk: Findings from the case-control IMAGINE-ID cohort in the United Kingdom

Samuel J.R.A. Chawner PhD, Michael Owen FRCPsych, Peter Holmans PhD, Lucy Raymond FRCP, David Skuse MRCPsych, Jeremy Hall MRCPsych, View ORCID ProfileMarianne van den Bree PhD
doi: https://doi.org/10.1101/535708
Samuel J.R.A. Chawner PhD
aMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael Owen FRCPsych
aMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Holmans PhD
aMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lucy Raymond FRCP
bDepartment of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Skuse MRCPsych
cInstitute of Child Health, University College London, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeremy Hall MRCPsych
aMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marianne van den Bree PhD
aMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Marianne van den Bree PhD
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Background A variety of Copy Number Variants are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). We aimed to characterise the impact of ND-CNVs on childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes.

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 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.

Funding The Medical Research Council and the Waterloo Foundation

Evidence before this study Several Copy Number Variants (CNVs) have been associated with high risk of development of child and adult neuropsychiatric disorders. Increasingly young children with developmental delay referred for genetic testing are being diagnosed with neurodevelopmental and psychiatric risk CNVs (referred to as ND-CNVs hereafter). It remains unclear whether different genotypes are associated with specific cognitive and behavioural phenotypes or whether these outcomes are non-specific. We searched PubMed for English language studies published from database inception until January 10th, 2019 that investigated the relationship between CNVs and cognitive and behavioural outcomes. Search terms included “CNV”, “genomics”, “1q21.1”, “2p16.3”, “NRXN1”, “9q34”, “Kleefstra Syndrome”, “15q11.2”, “15q13.3”, “16p11.2”, “22q11.2”, “psychiatry”, and “cognition”. Preliminary studies have indicated that deletions and duplications at the same loci may differ in cognitive and behavioural phenotypes. However, to date, there have been limited studies that contrasted the phenotypes of ND-CNVs across several loci on a range of cognitive and behavioural domains.

Added value of this study We found that young people carrying a ND-CNV were at considerably increased risk for neuropsychiatric disorder and impairments across a range of neurodevelopmental, psychopathological, cognitive, social, sleep and motor traits. Within ND-CNV carriers, comparisons between genotypes indicated moderate quantitative and qualitative differences in overall phenotypic profile, with evidence that severity of impairment was similar across all genotypes for some traits (e.g. mood problems, sleep impairments, peer problems, and sustained attention) whereas for other traits there was evidence of genotype specific effects on severity (e.g., IQ, spatial planning, processing speed, subclinical psychotic experiences, ASD traits, motor coordination total psychiatric symptomatology, particularly anxiety, ADHD, and conduct related traits). However the proportion of variance explained by genotype was low, 5-20% depending on trait, indicating that overall ND-CNVs lead to similar neurodevelopmental outcomes. It is important that genotype-phenotype relationships are viewed through a developmental lens as some phenotypic outcomes were found to be associated with age.

Implications of all the available evidence Our work highlights that children who carry a ND-CNV represent a patient group that warrants clinical and educational attention for a broad range of cognitive and behavioural impairments and that commonalities in clinically relevant neurodevelopmental impairments exist across ND-CNVs. This group of young people could benefit from the development of a general care pathway, to which genotype-specific recommendations can be added where needed. Our work indicates that the relationship between genotype and neurodevelopmental phenotype is complex and that future research will need to take a global systems approach and not be narrowly focused on single phenotypes.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Back to top
PreviousNext
Posted March 13, 2019.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Genotype-phenotype relationships in children with Copy Number Variants associated with high neuropsychiatric risk: Findings from the case-control IMAGINE-ID cohort in the United Kingdom
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Genotype-phenotype relationships in children with Copy Number Variants associated with high neuropsychiatric risk: Findings from the case-control IMAGINE-ID cohort in the United Kingdom
Samuel J.R.A. Chawner PhD, Michael Owen FRCPsych, Peter Holmans PhD, Lucy Raymond FRCP, David Skuse MRCPsych, Jeremy Hall MRCPsych, Marianne van den Bree PhD
bioRxiv 535708; doi: https://doi.org/10.1101/535708
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Genotype-phenotype relationships in children with Copy Number Variants associated with high neuropsychiatric risk: Findings from the case-control IMAGINE-ID cohort in the United Kingdom
Samuel J.R.A. Chawner PhD, Michael Owen FRCPsych, Peter Holmans PhD, Lucy Raymond FRCP, David Skuse MRCPsych, Jeremy Hall MRCPsych, Marianne van den Bree PhD
bioRxiv 535708; doi: https://doi.org/10.1101/535708

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (3609)
  • Biochemistry (7585)
  • Bioengineering (5533)
  • Bioinformatics (20825)
  • Biophysics (10344)
  • Cancer Biology (7995)
  • Cell Biology (11653)
  • Clinical Trials (138)
  • Developmental Biology (6617)
  • Ecology (10224)
  • Epidemiology (2065)
  • Evolutionary Biology (13639)
  • Genetics (9557)
  • Genomics (12856)
  • Immunology (7930)
  • Microbiology (19568)
  • Molecular Biology (7675)
  • Neuroscience (42182)
  • Paleontology (308)
  • Pathology (1259)
  • Pharmacology and Toxicology (2208)
  • Physiology (3271)
  • Plant Biology (7058)
  • Scientific Communication and Education (1295)
  • Synthetic Biology (1953)
  • Systems Biology (5433)
  • Zoology (1119)