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Genetic Risk Factors for PTSD: a Gene-Set Analysis of Neurotransmitter Receptors

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Genetic Risk Factors for PTSD: A Gene-Set Analysis of Neurotransmitter Receptors Michael Lewis Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Psychology Russell T. Jones Bruce H. Scarpa-Friedman Margaret T. Davis Rachel A. Diana May 12, 2020 Blacksburg, VA Keywords: PTSD, Gene-set analysis, GSA-SNP2, Neurotransmitter receptors, serotonin, glutamate, intracellular signaling Genetic Risk Factors for PTSD: A Gene-Set Analysis of Neurotransmitter Receptors Michael Lewis Abstract (Academic) PTSD is a moderately heritable disorder that causes intense and chronic suffering in 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 variations 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. Genetic Risk Factors for PTSD: A Gene-Set Analysis of Neurotransmitter Receptors Michael Lewis General Audience Abstract 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. iv DEDICATION To my father, Richard Allen Lewis. Thank you for everything you did to instill in me the work ethic needed to confront the challenges of a Ph.D. More importantly, thank you for showing me the power of love and kindness. I strive every day to put into practice the wisdom and caring you have bestowed upon me to. Though you are no longer here in person, you are always present in spirit and in my memory. I will forever cherish the countless happy memories of our times together. To my mother, Cynthia Theresa Lewis. Thank you for your immeasurable sacrifices and support, during both good times and bad. Had you not been there to encourage me, I do not believe that I would have attempted a Ph.D., let alone reached this particular milestone. Your continued presence in my live is a blessing each day and I am grateful for the countless lessons you have taught me, memories we have made together, and memories we continue to make. To my brother, Patrick Terrence Coyle. Thank you for the inspiration and advice you provided in paving the way for me to begin my career at Virginia Tech. As our career paths diverge, I remain grateful to you for guiding me to the start of the trail and for your continued advice, support, and friendship. To my partner, Anne Stewart Deekens. Thank you for adding immense joy to my life and for helping me become a better and more balanced person. Of the many blessings my time in Blacksburg have bestowed upon me, your presence in my life is by far my favorite. I cannot wait to begin our life together in Boston. Finally, thank you to the friends and lab mates whose support and advice has been invaluable throughout these years. In particular, I would like to thank Benjamin Biermeier- Hanson and Connor Sullivan. v ACKNOWLEDGMENTS To my advisor, Russell T. Jones, thank you for your guidance and mentorship throughout graduate school. I cannot tell you how grateful I am that you believed in me and supported my ambition to seek a Ph.D. in biological psychology. I feel truly grateful to have had an advisor who not only supports me as an academic, but also as a person. I look forward to remaining friends for years to come. To Bruce H. Friedman, thank you for opening the door for me to biological research by adopting me into the Mind Body lab. Your mentorship and support were critical in successfully transitioning to biological psychology and in acquiring skills in psychophysiology that I will apply in postdoc and beyond. To Margaret T. Davis, thank you for your guidance and mentorship. Your encouragement gave me the necessary confidence to pursue molecular research. You have imparted lessons and shaped skills that will have an imprint on my work throughout my career. I cannot tell you how grateful I am that you adopted me as a mentee. To Rachel A. Diana, thank you for helping to spark my interest in neuroscience. The assignments and discussions in your class were the beginning of my journey into molecular research and provided me with a model to emulate when I began teaching. I am forever grateful for the wisdom and knowledge each of you have bestowed upon me and I look forward to continuing to grow my relationship with each of you. Finally, thank you to Maddy Ryan and Marcus Nguyen for your important contributions to data organization and to Aiden England for your invaluable contribution to data cleaning in Java. vi Table of Contents 1.0 – Introduction ....................................................................................................................... 1 1.1 – PTSD: Public Health Impact and Importance of Genetic Risk Factors ............................. 3 1.2 – Genetics
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  • G Protein-Coupled Receptors

    G Protein-Coupled Receptors

    www.aladdin-e.com Address:800 S Wineville Avenue, Ontario, CA 91761,USA Website:www.aladdin-e.com Email USA: [email protected] Email EU: [email protected] Email Asia Pacific: [email protected] G PROTEIN-COUPLED RECEPTORS Overview: The completion of the Human Genome Project allowed the identification of a large family of proteins with a common motif of seven groups of 20–24 hydrophobic amino acids arranged as a-helices. Approximately 800 of these seven transmembrane (7TM) receptors have been identified of which over 300 are non-olfactory receptors (see Fredriksson et al., 2003; Lagerstrom and Schioth, 2008). Subdivision on the basis of sequence homology allows the definition of rhodopsin, secretin, adhesion, glutamate and Frizzled receptor families. NC-IUPHAR recognizes Classes A, B, and C, which equate to the rhodopsin, secretin, and glutamate receptor families. The nomenclature of 7TM receptors is commonly used interchangeably with G protein-coupled receptors (GPCR), although the former nomenclature recognises signalling of 7TM receptors through pathways not involving G proteins. For example, adiponectin and membrane progestin receptors have some sequence homology to 7TM receptors but signal independently of G proteins and appear to reside in membranes in an inverted fashion compared to conventional GPCR. Additionally, the NPR-C natriuretic peptide receptor (see Page S195) has a single transmembrane domain structure, but appears to couple to G proteins to generate cellular responses. The 300+ non-olfactory GPCR are the targets for the majority of drugs in clinical usage (Overington et al., 2006), although only a minority of these receptors are exploited therapeutically.