Developing a pathway from genetic locus to gene for complex traits in rodents

Objectives: The highly polygenic architecture of psychiatric disorders, consisting of thousands of independent effects each contributing a small amount to disease risk poses a challenge for understanding how information about genetic risk loci can be turned into mechanistic insight into disease pathophysiology. The solution proposed here is to obtain information in experimental systems where it will be possible to observe genetic effects operating on both behavior and the underlying circuitry. We aim to identify genes that mediate variation in unconditioned and conditioned responses to fearful stimuli, fear-related behaviors whose origins are now known at cellular resolution, thanks to the deployment of optogenetics, high-resolution microscopy and electrophysiology in freely moving rodents. Conservation of mechanisms across species means that insights will be directly relevant to a group of the most common psychiatric illnesses, the anxiety disorders, for which available treatments are addictive, inconsistently effective and associated with significant side effects. Crucially, our findings will make it possible to determine how genetic perturbations result in circuit changes, thereby giving clues as to how those perturbations can be used to inform the development of new therapies. Combining high resolution mapping, near complete catalogs of genetic variants in rodents, and a method to knock out genes in any strain, the proposal deploys the quantitative trait locus (QTL) knockout-interaction test, to identify genes.