Kaela Kuitchoua, Winner of the 2019 Three-Minute Talks Competition
Kaela Kuitchoua: Hello, my name is Kaela Kuitchoua. Schizophrenia is a devastating neuropsychiatric illness that affects about one percent of the population and is up to 80 percent heritable. People with schizophrenia experience severe deficits in cognition such as impaired working memory.
Schizophrenia and cognition are both thought to be polygenic, that is, influenced by multiple genes, but their heritability is still not fully understood. We can examine the genetic underpinnings of cognition by using genome-wide association studies.
For example, this is a genome-wide association for general cognition, which shows multiple genetic loci that are significantly associated with cognitive tasks when looking across the entire genome. We can assign weights to these loci based on the strength of their association to a complex trait, in this case, general cognition, to create polygenic scores for each individual. We can then use the polygenic scores that we create to examine the relationship between genes and other factors such as brain activation during cognitive tasks.
We hypothesized that there would be a relationship between polygenic score for general cognition and brain activation measured with fMRI during our working memory task. Since both cognition and brain activation are impaired in schizophrenia, we expected this relationship to be different between people with Schizophrenia and healthy controls. We created polygenic scores for general cognition based on this genome wide association study, and we controlled for age, sex, task performance, and ancestry related, genetic components.
We found a significant interaction here in this part of the prefrontal cortex. The interaction indicated that the relationship between polygenic score for general cognition and brain activation varied in a diagnosis specific manner. We extracted data from this prefrontal cluster in order to look more closely at the relationships with polygenic score within each diagnostic group.
Here we show the association of brain activation from the prefrontal cluster and polygenic score for cognition in people with Schizophrenia. The data showed a moderate positive relationship with the variance explained of eight percent indicating that a lower polygenic score for cognition was associated with less activation.
However, in our healthy control group, this relationship was not seen. The association of polygenic score for general cognition with working memory activation to point to a rate-limiting factor for prefrontal function in people with Schizophrenia, but not healthy controls.
The more we understand how genetics drive phenotypes like cognition in schizophrenia, the closer we will be to identifying neurogenetic factors mediating the illness.