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Approved research

The Impact of Second-hits on Putative Psychiatric Phenotypes in Synaptopathy CNV Carriers in the UK Biobank.

Principal Investigator: Dr Lorna Lopez
Approved Research ID: 48915
Approval date: April 10th 2019

Lay summary

Aims: The aim of this project is to understand why carriers of genetic variants which disrupt cellular structures important for brain circuitry show such variable psychiatric phenotypes (behaviours) i.e. some show little or no symptoms whereas others show distinct psychiatric symptoms. The genetic variants and cellular structures in question are copy number variants (CNVs) and synapses respectively. Many Neuropsychiatric Disorders (NPDs) are caused by disruptions in synaptic properties (also known as Synaptopathies). We will test a popular current hypothesis that genetic variants in other regions of the genome, i.e. second-hits, cause this variability (heterogeneity) in carrier phenotypes. Second hits in this project will be defined as independent, single-nucleotide polymorphisms (SNPs), i.e. single DNA-base changes, in brain expressed genes significantly associated with NPDs. How can the phenotypic impact of second-hits be measured? Our strategy will be to analyse the burden (the amount) and permutations of second-hits in Synaptopathy CNV carriers in the UK Biobank. By doing so, we believe we can estimate the phenotypic impact of second-hits in carriers. Scientific rationale: CNVs are large genomic deletions/duplications which can encompass one or many genes. As mentioned above, they are associated with heterogeneous phenotypes including many Neuropsychiatric Disorders (NPDs) e.g. Autism, Schizophrenia, Epilepsy. Disruptions in synaptic pathways, referred to as 'Synaptopathies', are frequently observed in many NPDs. Synaptopathies are diseases and disorders caused by dysfunctions in synapses due to disruptive variants in synapse-related genes. Synapses are important cellular structures needed for neuronal connections, signalling and neural circuitry. Although Synaptopathy CNV carriers can share deletions/duplications in synapse-related genes, they display extremely heterogenous phenotypes i.e. some carriers are asymptomatic whereas others have NPD phenotypes. The genetic reason underlying how these heterogenous phenotypes arise remains unknown. Here we test the hypothesis that genetic variants in other genomic regions, i.e. second-hits, associated with brain development and function govern the phenotypic outcome. Project duration: The project is estimated to take up to 24 months, including the analysis and reporting of findings. Public impact: Our research will test a current hypothesis that the variable/heterogeneous phenotypes of carriers are governed by second-hit variation. Testing this hypothesis could improve current knowledge of NPD-associated Synaptopathy CNVs for researchers, clinicians and genetic counsellors, which could potentially lead to improved diagnoses. This research will build on previous work on CNVs in the UK Biobank.