Dissecting the effects of genomic variants in rare CNVs
Research type
Research Study
Full title
Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neurospsychiatric disorders
IRAS ID
254310
Contact name
Marianne van den Bree
Contact email
Sponsor organisation
Cardiff University
Duration of Study in the UK
6 years, 9 months, 31 days
Research summary
Copy number variants (CNVs) at chromosomes 22q11.2 and 16p11.2 are associated with significant risk for neuropsychiatric disorders across the lifespan. The clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders, including Attention Deficit Hyperactivity Disorder (ADHD), Anxiety Disorders (AD), Autism Spectrum Disorders (ASD), Schizophrenia (SZ) and Psychosis Spectrum (PS) features. The developmental course of clinical phenotypic expression is of interest as it generalizes to idiopathic populations, and thus provides a window to elucidating the genetic architecture of major neuropsychiatric disorders. Notably, while developmental delay (DD) and intellectual disability (ID) are evident in these CNVs, the neurobehavioral dimensions implicated are present in individuals with mild DD and no significant ID. Understanding the molecular and neurobiological mechanisms through which these variants give rise to psychopathology is required in order to develop personalized approaches to treatment. Knowledge of the molecular, environmental and clinical predictors of adverse outcome in these syndromes could facilitate early intervention and lead to better outcomes.
Based on evidence from our previous studies and the literature, we propose that: (1) CNVs exert a large main effect on psychopathology; (2) the nature and degree of psychopathology is multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors; and (3) analysis of additional genomic data on rare and common variants, together with the use of dimensional measures of psychopathology, can elucidate underlying mechanisms of genetic complexity and facilitate more accurate risk prediction.
We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition, and their genetic and environmental modifiers to elucidate the architecture of risk for neuropsychiatric disorders in patients with rare CNVs. We will investigate a large cohort of 2000 individuals who carry reciprocal CNVs (deletions and duplications) at chromosomes 22q11.2 and 16p11.2. Prospective evaluation with a consistent set of dimensional measures relevant to neuropsychiatric disorders, as well as categorical diagnoses of ADHD, AD, ASD, and SZ, will be applied. Recruitment for prospective phenotyping will take advantage of existing large cohorts that carry these reciprocal CNVs. Our genomic analysis will utilize existing genetic data from the largest available case-control samples diagnosed with SZ, ASD, and ADHD. For many CNV carriers, DNA, whole genome sequencing data, as well as a range of phenotypic measures are already available. Finally, the availability of common variant genotypes for a subset of family members will allow us to complement our primary analysis by exploring models of complex genetic inheritance in extended pedigrees that carry CNVs.
Specific Aims
1. Apply common dimensional phenotypic measures across CNV syndromes that tap symptoms and cognitive domains relevant to neuropsychiatric disorders. We will apply developmentally sensitive, quantitative web-based measures of social-emotional processing (real-world social behavior, theory of mind, emotion recognition), cognition (IQ, memory, attention, processing speed), and PS to:
1a. Validate dimensional measures related to PS in a lifespan context. 1b. Conduct both cross-sectional and longitudinal comparisons of these dimensional measures across CNV groups, to better understand the specificity of the impact of genomic variants. 1c. Examine family and environmental factors that contribute to the heterogeneity of presentation and developmental course in CNV carriers.
2. Investigate the genetic determinants of psychopathology in CNV carriers.
2a. Perform whole genome sequencing of 2000 deeply phenotyped new patient samples (500 carriers in each of the four CNV groups). Sequence, structural and repeat variation will be characterized using best practice tools for raw sequence processing and customized computational methods for variant calling developed by the project team. 2b. Investigate genetic factors that influence variation in dimensional measures, including rare variant burden and polygenic risk. 2c. We will exploit common variant genetic data already available for a subset of trio and multiplex families that carry CNVs to further investigate the contribution of assortative mating, the effect of the main CNV, inherited, secondary large CNVs and common polygenic variation to co-morbidities in the proband.
3. Develop and validate risk prediction models by integrating genetic, environmental and clinical correlates of neuropsychiatric disorders such as AD, ADHD, ASD, SZ- PS, using a lifespan approach.
3a. Expand the development of rare variant scoring models for estimating risk for neuropsychiatric disorders, applying models we have developed to estimate the effect size of rare variants on cognitive and behavioral traits. 3b. Develop and validate machine learning classification methods for estimation of neuropsychiatric risk in individuals.
4. Establish common phenomic and genomic resources, in collaboration with NIMH, and place all data and algorithms in the public domain.REC name
East Midlands - Leicester Central Research Ethics Committee
REC reference
19/EM/0287
Date of REC Opinion
24 Oct 2019
REC opinion
Further Information Favourable Opinion