<p> Impairments in various aspects of language, including the manipulation and comprehension of verbal and written language, are common in pediatric populations. Some disorders of language are secondary to other clinical presentations, while others, such as dyslexia (or reading disability [RD]), language impairment (LI), speech sound disorder (SSD), and autism spectrum disorders (ASD), have primary deficits in language skills. Each of these is a distinct disorder with unique clinical presentations and deficits. For instance, children with RD have deficits in reading and the use of written language, while those with LI have deficits in the manipulation and comprehension of verbal language. Additionally, children with SSD have difficulties in the production of speech sounds, while children with ASD may have delays or regressions in language and an inability to use complex, proper syntax and pragmatics. However, there is substantial comorbidity of these disorders, as children affected with one of these disorders are more likely to have or develop another disorder than their typically developing peers. These 'disorders&mdash;RD, LI, SSD, and ASD&mdash;are complex traits, with significant environmental and genetic components contributing to each. Similar to their phenotypic relationships, there is limited evidence that these disorders may share genetic contributors. In fact, these shared genetic components may explain the common phenotypic comorbidities of these disorders. Therefore, the overall goal of this project is to determine whether and to what extent RD, LI, SSD, and ASD share genetic associations with the hypothesis that these disorders have common genetic contributors. To accomplish this goal, I assess whether genetic associations were shared among these disorders or specific to individual disorders. First, I expand the association of the RD environmental risk factor, prenatal exposure to nicotine, to include LI and show the association of dopamine-related genes <i> ANKK1</i> and <i>DRD2</i> to LI. Second, two RD risk genes, <i> DCDC2</i> and <i>KIAA0319</i>, located within the DYX2 locus on chromosome 6p22, show associations with both LI and SSD. Third, I identify <i> ZNF385D</i> as a novel risk gene for subjects affected with comorbid RD and LI. I also assess the neuroimaging implications of DYX2 genes and <i> ZNF385D</i>, specifically in regards to cortical thickness, fiber tract volume, and fractional anisotropy. Finally, two LI risk genes, <i>ATP2C2 </i> and <i>CMIP</i> located within the SLI1 locus on chromosome 16, are associated with language skills of subjects with ASD. Taken together, these results characterize the relationship of previously identified risk genes to other related language disorders and identify novel risk genes that specifically contribute to language comorbidity. Shared genetic associations among these language disorders appear to be commonplace as opposed to the exception. However, the question remains of how these genetic variants interact with each other and other genes/exposures to ultimately lead to one or more of these language deficits seen clinically.</p>

<p> The worm <i>Caenorhabditis elegans</i> is a well-studied model organism in numerous aspects of its biology. This small free living nematode has less than 1,000 cells, but shows clear conservation in both signaling and behavior to mammals in aspects of appetite control. This is of importance to humans, where failure of appetite control is a major factor in the unprecedented obesity epidemic that we see today. </p><p> In general, worm behavior reflects its internal nutritional state and the availability and quality of food. Specifically, worms show a behavioral state that mimics aspects of the mammalian behavioral satiety sequence, which has been termed satiety quiescence. We have used locomotion tracking and Hidden Markov Model analysis to identify worm behavioral state over time, finding quiescence along with the established worm locomotive behaviors roaming and dwelling. Using this analysis as well as more conventional cell biology and genetic approaches we have further investigated satiety signaling pathways. We have found that the neuron ASI is a major center of integration of signals regarding the internal nutritional state of the worms as well as the nutritional content of its environment. Our results show that cGMP causes levels of the TGF&beta; ligand to be increased in fasted worms, which is then released and binds to its receptor on the RIM and RIC neurons. This signaling connects nutritional state to behavioral response, promoting the sleep-like behavioral state satiety quiescence. Additionally, we have begun a candidate approach examining several other groups of signaling molecules for potential roles in satiety quiescence signaling including cannabinoids, multidrug resistance proteins, and neuropeptides. The result of this investigation is a better understanding of mechanisms of satiety quiescence signaling as well as a new tool that provides highly quantitative, unbiased, and automated data to aid in our ongoing work.</p>