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Endophenotypes of Executive Control: A Reverse Genetic Approach


Neurogenetic disorders with distinct genetic etiologies and known psychiatric phenotypes present a compelling model to study the links between genotype and phenotype. In recent years, the study of quantitative endophenotypes has become increasingly relevant in garnering a comprehensive understanding of psychiatric dysfunction. Neurofibromatosis Type 1 (NF1) and 22q11.2 Deletion Syndrome (22q11DS) are two compelling examples of neurogenetic disorders that are highly penetrant for neuropsychiatric phenotypes, and are also characterized by prefrontal cognitive dysfunction. We investigated endophenotypes of executive control in these populations, using a reverse-genetic approach.

In Chapter 2, we measured risk-taking behavior using a child-friendly gambling task in patients with NF1 and controls (N=29 NF1, 23 controls). We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with risky decision making, as well as age-associated changes in these behavioral and neural processes. Behaviorally, patients with NF1 tended to made fewer risky decisions than controls. Neuroimaging analyses revealed significant hypoactivation of multiple brain regions involved in higher-order semantic processing and motivation (i.e., anterior cingulate, paracingulate, supramarginal, and angular gyri) in patients with NF1 relative to controls, in both decision-making and outcome phases of the task. We also observed atypical age-associated changes in neural activity in patients with NF1, such that during risk taking, neural activity tended to decrease with age in controls, whereas it tended to increase with age in patients with NF1. Findings suggest that developmental trajectories of neural activity during risky decision-making may be disrupted in youth with NF1.

In Chapter 3, we reviewed recent literature on the utility of studying endophenotypes of psychiatric illness in 22q11DS. We provided an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder’s heterogeneous presentation were reviewed. We discussed the use of how animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.

In Chapter 4, we investigated executive function and its relationship with structural neuroanatomy in patients with 22q11DS and matched controls (N=43 22q11DS, 43 controls), along with cognitive measures that tap behavioral regulation and metacognitive aspects of executive function. Behaviorally, patients with 22q11DS were impaired on multiple executive function measures. Right orbitofrontal cortical thickness showed a differential relationship between real-world executive function in patients with 22q11DS and controls. We also observed a group difference in the relationship between behavioral regulation and metacognition measures with thickness of ventral and dorsolateral prefrontal regions, respectively. Findings suggest that executive dysfunction characteristic of 22q11DS is underscored by altered prefrontal cortical structure.

In Chapter 5, we investigated gene expression levels and behavioral correlates in patients with 22q11DS and matched controls (N=56 22q11DS, 48 controls). Using real-time quantitative polymerase chain reaction (RT-qPCR), we measured gene expression levels of three genes that are hemizygous in 22q11DS (COMT, DGCR8, and ZDHHC8). We found decreased expression of all three genes in patients with 22q11DS. We found a positive relationship between age and COMT expression in patients with 22q11DS, but not in controls. We also investigated the relationship between gene expression levels and relevant cognitive measures related to executive function, and found interaction effects between group and IQ for DGCR8 and ZDHHC8. Lastly, we found a relationship between working memory and COMT expression in patients with 22q11DS, but not in controls. Results suggest that the relationships between gene expression and cognitive function may differ between patients with 22q11DS and controls.

Overall, the collected work provides insight into the use of endophenotypes of executive control in neurogenetic disorders. In clinical psychiatry, current methods for diagnosing psychiatric illness rely on clinical symptoms. Our research is in line with the NIMH RDoC framework, which supports the notion of studying intermediate endophenotypes in order to better diagnose and treat patients with psychiatric illness. Having a comprehensive understanding of the building blocks of psychiatric disease can lead not only to better methods of diagnosis, but also to better treatment strategies.

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