<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—RD, LI, SSD, and ASD—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>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:3580677 |
| Date | 27 June 2014 |
| Creators | Eicher, John Dickinson |
| Publisher | Yale University |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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