Identifying the spectrum of biomedical traits in adults with pathogenic copy number variants (CNVs)

Deletions and duplications of large stretches of chromosomes, known as copy number variants (CNVs), cause several neurodevelopmental disorders, such as schizophrenia, developmental delay and autism spectrum disorder. However, the full clinical spectrum associated with most of these CNVs has not yet been established and there is limited evidence of the impact of these CNVs in the general population, e.g. in apparently healthy carriers. We propose to identify the carriers of pathogenic CNVs in the full UK Biobank sample. We will then identify the cognitive deficits and common medical problems that are increased in carriers of each of these CNVs. The rarity of most pathogenic CNVs has so far prevented researchers from confidently establishing their full medical and neurocognitive consequences. Therefore it is currently impossible for genetic counsellors to give accurate advice to CNV carriers. Our research will provide the most comprehensive assessment of neuropsychiatric and common medical problems associated with known pathogenic CNVs. This will result in a greater understanding of the risks conferred by these CNVs for the development of diseases, and give clinicians the necessary information for diagnosing, counselling and treating the carriers of these CNVs. We will first generate a set of high quality CNVs from all participants in the UK Biobank cohort using the data from microarray genotyping already conducted by Affymetrix. (If UK Biobank calls the CNVs centrally, we can use these calls and just apply our quality control filtering). We will identify the individuals carrying pathogenic CNVs. Carriers of pathogenic CNVs will then be compared with the remaining participants, who are free of such CNVs, for neuropsychiatric problems (including cognitive performance), common medical conditions, and basic characteristics (e.g. weight and height), which can be affected by CNVs. We require genetic data from the full UK Biobank cohort. We also need a set of basic demographic and common health outcomes that could be affected by CNVs. These include neuropsychiatric outcomes such as epilepsy, psychosis, mood disorders, cognitive tests, educational indices, and self-reported medical/psychiatric conditions. When it becomes available, we would like to add the diagnostic codes from the primary care data, to supplement the self-reports. Carriers of these CNVs might have an increased rate of premature terminations and have fewer children, therefore we also want to collect the self-reported information on these outcomes.