Proj 4: Genetics (197-223)

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Molecular genetic studies of executive functions (EFs) examining the roles of dopamine-(DA) related genes have provided some support for the widely held view that DA modulates executive control. However, these studies have had little impact on current understanding of EFs, because they have usually only examined very few DA genes and have focused on gross executive control as measured by individual frontal-lobe tests, rather than separable, theoretically defined EFs identified in the cognitive literature. The goal of this project is to use molecular genetic analyses in concert with computational modeling to specify in more detail how the DA system regulates three correlated but separable EFs - inhibiting prepotent responses, updating working memory, and shifting mental sets. In doing so, it will begin to bridge current understanding of EFs across the psychological, computational, and neurobiological levels. The primary dataset will be existing EF data from 814 individual twins aged 17. Our multivariate analyses indicate that the three EF latent variables are highly heritable and reflect both common and unique genetic influences. This project will take the important next step of specifying how different DA-related genes influence the common and unique genetic variance in EFs. Specifically, we will (1) use computational models of EF tasks to both generate predictions and incorporate results for genetic analyses, with the goal of developing more detailed models of how the DA system dynamically regulates executive control; (2) examine the extent to which polymorphisms in a large set of DA-related genes contribute to variance in each EF, and whether the contributions differ for the three EFs; and (3) conduct parallel analyses on data from identical or comparable EF tasks collected as part of three ongoing studies of subjects selected for learning, conduct, and/or attention problems. Comparison of the results for the clinically extreme groups versus unselected samples will provide an additional source of information about how DA modulates EFs and serve as a foundation for future translational research in these and other clinical samples that are currently being collected by Center investigators and their collaborators. Hence, the results of the proposed study will contribute to a better understanding of how DA modulates different EFs in normal young adults, with broad implications for public health issues related to everyday cognitive functioning and EF deficits in both healthy and clinical populations.