PTSD is a moderately heritable disorder that causes intense and chronic suffering in many afflicted individuals. The pathogenesis of PTSD is not well understood, and genetic mechanisms are particularly elusive. Neurotransmitter systems are thought to contribute to PTSD etiology and are the targets of most pharmacotherapies used to treat PTSD, including the only two FDA approved options and a wide array of off-label options. However, the degree to which variation in genes which encode for and regulate neurotransmitter receptors increase risk of developing PTSD is unclear. Recently, large collaborative groups of PTSD genetics researchers have completed genome-wide association studies (GWAS) using massive sample sizes and have made summary statistics available for public use. In 2018, a new technique for high-powered analysis of GWAS summary statistics called GSA-SNP2 was introduced. In order to explore the relationship between PTSD and genetic variants in widely theorized molecular targets, this study applied GSA-SNP2 to manually curated neurotransmitter receptor gene-sets. Curated gene-sets included nine total "neurotransmitter receptor group" gene-sets and 45 total "receptor subtype" gene-sets. Each "neurotransmitter receptor group" gene-sets was designed to capture concentration of genetic risk factors for PTSD within genes which encode for all receptor subtypes that are activated by a given neurotransmitter. In contrast, "receptor subtype" gene-sets focused on specific subtypes and also accounted for intracellular signaling; each was designed to capture concentration of genetic risk factors for PTSD within genes which encode for specific receptor subtypes and the intracellular signaling proteins through which they exert their effects. Due to practical considerations, this work used summary statistics derived from a GWAS with far fewer participants (2,424 cases; 7,113 controls) than initially planned (23,212 cases; 151,447 controls). Prior to controlling for multiple comparisons, 7 of the investigated gene-sets reached statistical significance at the p ≤ .05 level. However, after controlling for multiple comparisons, none of the investigated gene-sets reached statistical significance. Due to limited statistical power of the current work, these results should be interpreted very cautiously. The current study is best interpreted as a preliminary study and is most informative in relation to refining study design. Implications for next steps are emphasized in discussion and nominally significant results are synthesized with the literature to demonstrate the types of research questions that might be addressed by applying a refined version of this study design to a larger sample. / Doctor of Philosophy / Though nearly all individuals will be exposed to a potentially traumatic event in their lifetime, only a small percentage will experience PTSD, which is a severe psychological disorder. Though genetics are known contribute to an individual's level of risk for developing PTSD, relatively little is known about which particular genetic differences are key. Neurotransmitter receptors are thought to contribute to the risk for PTSD and are a key aspect of medications for PTSD. However, little is known about whether genetic differences in neurotransmitter receptors contribute to risk for developing PTSD. Recently, large collaborative groups of PTSD genetics researchers have completed studies which investigate genetic risk factors from across the genome using massive sample sizes and have made the statistical output of these studies available to the public. In 2018, a new technique called GSA-SNP2 was created to help assist with efforts to analyze aspects of that statistical output that have not been previously analyzed. This study used GSA-SNP2 to analyze the degree to which groups of neurotransmitter receptor genes contribute to the risk of developing PTSD. Due to the coronavirus pandemic, the researcher did not have access to the computing power needed to analyze the initially planned data which included 23,212 individuals with PTSD and 151,447 individuals without PTSD. As a substitute, the current work is an analysis using statistical output data from a study which included 2,424 individuals with PTSD and 7,113 individuals without PTSD. Based on a level of statistical significance that is typically used in most psychological studies, seven of the investigated gene-sets contribute highly to the risk for PTSD. However, it was necessary to use a different threshold for statistical significance due to the testing of many different groups of genes. After making that adjustment, none of the investigated gene-sets reached statistical significance. Due to limited statistical power of the current work, these results should be interpreted very cautiously. The current study is best interpreted as a preliminary study and is most informative in relation to refining study design. Implications for next steps are emphasized in discussion and nominally significant results are synthesized with the literature to demonstrate the types of research questions that might be addressed by applying a refined version of this study design to a larger sample.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/99310 |
| Date | 08 July 2020 |
| Creators | Lewis, Michael |
| Contributors | Psychology, Jones, Russell T., Friedman, Bruce H., Diana, Rachel A., Davis, Margaret Taylor |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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