Imaging genetics in schizophrenia and bipolar disorder: Adjudicating neurocognitive endophenotypes

Schizophrenia and bipolar disorder are severe psychiatric conditions traditionally regarded as separate disease entities, although both are characterized by intermittent periods of disturbance in thought, motivation and affect. Heritability estimates for each condition suggest that a combination of both genetic factors and environmental stressors play a role in their development, but the precise genetic contribution to these disorders remains unknown. Convergent evidence from genetic epidemiology, linkage, association, and gene expression studies implicate shared genetic susceptibility in association with co-occurring mood and psychotic symptoms. Implicated loci include polymorphisms on the Catechol O-methyltransferase (COMT) gene, which has direct effects on dopamine function in the prefrontal cortex, and polymorphisms on the Brain Derived Neurotrophic Factor (BDNF) gene, associated with human memory functions of the hippocampus, and emotion processing of the amygdala. In this study we consider these emerging genetic commonalities in the context of parallel evidence for shared cognitive impairments in schizophrenia and bipolar disorder, most consistently with regard to prefrontal executive (working memory) function, and more recently in the domain of emotion processing.

Our general hypothesis is that shared genetic vulnerability may be associated with common neurocognitive endophenotypes in schizophrenia and bipolar disorder. Endophenotypes refer to heritable traits positioned intermediately between genes and clinical phenotypes, which may reflect more elementary processes, requiring the interaction of fewer genes to produce variation in these traits compared to the number potentially involved in producing complex psychiatric phenomena. While we predict that there may be common cognitive abnormalities arising from shared genetics in schizophrenia and bipolar disorder, an important caveat that we will investigate in this project reflects the possible modulation of genetic effects upon cognition by physiological responses to stress associated with hypothalamic-pituitary-adrenal (HPA) axis function. This hypothesis is based on evidence linking HPA dysfunction with neurocognitive impairment in these disorders, and on the basis of differential neural responses demonstrated in schizophrenia and bipolar disorder when processing emotional stimuli, despite comparable deficits in behavioural performance.

The specific aims of this project are therefore to integrate cognitive brain imaging, physiological (salivary cortisol), and genetic data in order to examine (a) whether shared genetic contributions to schizophrenia and bipolar disorder are associated with neurocognitive endophenotypes (i.e., brain function elicited during working memory and emotion processing tasks), and (b) whether genetic associations with working memory and emotion processing are modulated by HPA function. Our strategy of investigating shared and distinct neurocognitive endophenotypes for bipolar disorder and schizophrenia will advance our understanding of the biological bases of these conditions, with implications for the validity and clarification of current psychiatric nosology, and will facilitate early detection of cognitive markers of vulnerability to psychosis, regardless of specific diagnosis. 

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