My laboratory is undertaking a series of studies to find out how genetic variants alter behavior, with a particular focus on anxiety and depresson. We do this through genetic engineering and genetic mapping studies in mice, and through the analysis of large cohorts of human subjects, working to identify the relevant genetic variants and the genes upon which they act, as a starting point to exploring how genes influence behavior.
1- Over the last 20 years many thousands of genetic loci that contribute to behavioral variation have been identified in mice and rats. This is the first step towards discovering genes, which in turn are expected to provide new insights into the biology of behavior, and, when the behavior is related to psychiatric disease, to aid the development of new therapies. Yet remarkably few genes have been unequivocally identified as causal. This project applies resources and techniques my laboratory developed, in particular the use of outbred animals for high resolution mapping and catalogs of genetic variants, to deliver an efficient and robust method, the knockout-interaction test, to identity genes at loci contributing to behavioral variation, particularly anxiety and depression.
2- There is a remarkable gap in our knowledge in the relationship between genes and behavior. On one hand we know the position in the genomes of thousands of genetic variants that alter the risk of psychiatric disease, or alter human personality and behavior (including our sleeping and coffee preferences); on the other we have powerful tools to identify and activate neuronal circuits in mammalian brains - we know, and can see, that activity in those circuits results in behavior. But no one knows how genes affect circuit funtion. By taking advantage of the wide-ranging effects of genetic variation on neural circuits and behavior, we aim to test the effect of genetic variation on circuit mechanism and hence develop new theories as to how the brain controls behavior
3- Major depressive disorder is the commonest psychiatric disorder and is recognized as the leading cause of disability worldwide. Yet depression has not benefited from the genetic advances that have begun to transform our understanding of other conditions. We work with colleagues around the world to identify genetic variants that alter the risk of depression, using large cohorts of patients with recurrent depression.
Jonathan Flint has been a pioneer in the genetics of behaviour. He showed that behaviour, and psychiatric diseases are genetically tractable targets, and he has made key advances in identifying their molecular underpinnings, particularly with his work on structural variants. His genome-wide analyses of behaviour in rodents, precursors to GWAS in humans, revealed the polygenic architecture of behavior, arising from the joint action of many loci of small effect, a key insight for the design and interpretation of genetic studies in psychiatry.
His work has had clinical relevance: probes developed in his laboratory are now part of standard screening protocols for intellectual disability across the world; his work on determining the causal pathway from mutation to behavioural phenotype resulted in the discovery of an important and unexpected cause of a human genetic disorder (neuronal migration defects), again with benefits for patients and families.
He developed and pioneered novel approaches in mouse genetics, championing the use of multi-parental lines and outbred mice. Together with the widely used sequence data of classical inbred strains, these ideas and resources have transformed complex trait analysis in rodents.
His insistence on the importance of careful delineation of phenotypes in psychiatric genetics resulted in his successful genetic analysis of major depression, and has opened new avenues to understanding the origins of the world’s leading cause of disability. Such work is necessary to develop new ways of treating patients.
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