Ananda B. Amstadter, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Traumatic event exposure is associated with elevated risk of a range of mental-health problems such as posttraumatic stress disorder (PTSD) and major depressive disorder (MD). These phenotypes are major public health problems associated with an increased risk of morbidity and mortality. Although considerable effort has been given to identify correlates of risk and resilience, a high percentage of variance remains unexplained. Further, psychiatric genetic investigations have been mixed in their ability to identify direct effects of genotypes on disorder phenotypes. Therefore, the need is high for novel approaches to examining these relationships to inform models of risk and resilience. The primary objective of this project, directly in accordance with the research priorities of the NIMH Division of Neuroscience and Basic Behavioral Sciences (DNBBS), is to examine the relationship between monoamine transporter genes and psychopathology in two populations (disaster- and combat-exposed) using a candidate gene by environment interaction (GxE) model. The candidate's research plan is two fold. First, she will analyze DNA samples from her sponsor's NIMH-funded population-based sample of 600 adult Floridians affected by the 2004 Atlantic [unreadable] hurricane season. Aside from feasibility analyses and major analyses relating to the 5-HTTLPR, these DNA data remain virtually unstudied, thereby providing the basis of the primary aim of this proposal. As these data are population based, the proposed project not only addresses the DNBBS's priority of identifying biological markers of risk and resilience of mental disorders, but also allows for investigation of genetic variants among ethnically diverse populations. Second, the candidate will build upon her co-sponsor's NARSAD/VAMC funded pharmacogenetic study of 300 combat-exposed veterans, which is currently underway. The candidate will collect samples, extract DNA, and genotype samples for the monoamine transporter genes analyzed in the Florida disaster sample to investigate the relationship between monoamine transporter genes and disorder phenotypes in veterans. By examining GxE interactions this project will assess whether relations between trauma exposure and mental health phenotypes are moderated by candidate genes identified in previous GxE studies, as well as genes identified with phenotypic expression risk and/or the neurobiology of stress response systems. PUBLIC HEALTH RELEVANCE: This project has potential public health benefits by identifying specific genotypes that moderate the relation between stressor exposure and mental health outcomes in two distinct trauma exposure groups. Findings from the proposed research would aid in identifying persons in need of intervention in the aftermath of a traumatic event. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Military personnel exposed to combat-related traumatic events, particularly those who develop posttraumatic stress disorder (PTSD), have a higher incidence of problematic drinking. However, little is known about the relationship between trauma, PTSD, and drinking in "emerging adults" (ages 21-30 years), in spite of this age group being at highest risk of developing subsequent drinking problems. The proposed clinical laboratory project will use a three group design. The target OIF/OEF population will have no trauma exposure [Control group], combat trauma exposure without PTSD [TE group], and combat trauma exposure with PTSD [PTSD group]. The type of traumatic event exposure history included will be limited to combat- related traumatic events that are interpersonal in nature. This project will use a well-established clinical laboratory paradigm of stress induction employed by our group, the Trier Social Stress Test (TSST), to investigate the role of a history of exposure to combat trauma on reactivity to the TSST and on stress- induced voluntary drinking. Subjects will not meet diagnostic criteria for alcohol dependence. Half of each group will receive the TSST and the other half will be randomized to the no stress condition. Using subjective as well as biological indices of stress, the first specific aim examines the effect of combat trauma history on stress reactivity, using subjective, neuroendocrine, and physiological measures of stress. The second specific aim will examine the effect of combat trauma history on subsequent drinking behavior and subjective response to alcohol using established procedures in a clinical laboratory paradigm. Exploratory analyses will also be conducted to examine the correlation between combat trauma history group and subjective response to stress, and combat trauma history group and drinking. Two additional exploratory analyses will evaluate the effect of the personality trait of distress tolerance (high and low), and the effect of carrying the 'S'or the rare 'LG'allele of the 5-HTTLPR polymorphism on the stress response and on voluntary drinking following stress induction. This study will advance our understanding of the relationship between a history of combat-related traumatic events, stress, and drinking. The ultimate goal of this line of research is to identify "at risk" groups early in their drinking careers, before unhealthy drinking practices and/or dependence develop. This information has the potential to inform prevention and intervention alcohol research. PUBLIC HEALTH RELEVANCE: By providing data related to the interaction of stress and drinking from a relatively neglected group of subjects, young OIF/OEF adults between 21-30 who have been exposed to combat-related traumatic events it may be possible to prevent alcohol dependence from developing and, thereby, reduce the magnitude of costs to the individual and to society.

DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD) among adolescents exposed to disasters is prevalent and increases health morbidity and mortality. Although PTSD is common among youth exposed to traumatic stressors, is not present among all exposed youth. Disaster-exposed youth, in comparison to adults, are at significantly greater risk for PTSD, with symptoms often persisting for many months and years post-disaster;however, youth are drastically under-represented in post-disaster studies. Considerable effort, primarily in the adult literature, has been given to identify variables related to PTSD risk, but only about 20 percent of variance has been explained by psychosocial variables;thus, there has been interest in including genetic determinants into studies of PTSD. Despite moderate heritability estimates (30 percent) for PTSD, modern studies of genetic risk factors for PTSD are relatively few in number and psychiatric genetic investigations have been mixed in their ability to identify direct effects of genotypes on disorder phenotypes. Notably, there are no existant genetically informed studies of adolescent PTSD, a critical developmental phase. Therefore, the need is high for novel approaches to examining genetic and environmental moderators to inform models of risk and resilience in disaster exposed youth. Therefore, we are responding to Notice Number (NOT-OD-10-032) Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications (R01, R03, R15, R21, R21/R33, and R37) through the NIH Basic Behavioral and Social Science Opportunity Network (OppNet). The primary objective of this project, directly in accordance with the research priorities of the NIH OppNet (NOT-OD-10- 032), is to add genetic sampling to a funded R01 investigation of disaster-exposed youth. The parent project will recruit a population-based sample of 3,000 disaster exposed youth and their parents participating in an NIH-funded longitudinal, web-based intervention study (R01MH081056). Youth and parent participants will complete an initial phone-based assessment, where information regarding disaster exposure, other traumatic event experiences and incident characteristics, family-related variables, and PTSD and other mental health symptomatology will be gathered. OppNet funding will be used to expand the interview to include a larger range of possible environmental modifiers. During the baseline interview, adolescents will be asked to provide saliva samples for DNA analysis, which will also be conducted through use of OppNet funding. Participants will be sent a collection kit that they return via U.S. mail, methods we have successfully executed in a previous disaster-focused study. DNA will be extracted from saliva samples and candidate genes will be examined via the tagging SNP method and by assying specific variable number tandem repeats of genes reported in the extant literature to be relevant for PTSD. By examining GxE interactions this project will assess whether relations between candidate genes and PTSD are moderated by aspects of the environment. This project, by harnessing the behavioral and social data from the R01 with the biologic data from the OppNet funding, will afford a deeper understanding of the interplay between the environment and biology in the aftermath of a traumatic stressor. Additionally, this project has potential public health benefits of informing the knowledge of pathophysiology of PTSD which may lead to improved pharmacologic treatment targets. PUBLIC HEALTH RELEVANCE: Many youth are exposed to disasters and other potentially traumatic events that can produce posttraumatic stress disorder (PTSD);however, not all exposed individuals develop PTSD, so information is needed about how biologic and environmental factors interact to increase or decrease risk of PTSD post-disaster. This project addresses this issue by collecting DNA from adolescents who were exposed to a disaster, allowing for examination of gene by environment interactions for adolescent PTSD. By testing whether relevant candidate genes and features of the environment modify the impact of exposure to traumatic events, we will advance basic science knowledge that will deepen our understanding of the causes of pediatric PTSD, which may inform secondary prevention or intervention of PTSD in youth.

Project Summary The purpose of the present K02 Independent Scientist Award is threefold: first, to provide structured career development activities in psychiatric, statistical, and molecular genetics, second, to deepen my knowledge of alcohol-related phenotypes, and third, to apply these skills to the analysis of the rich genomic data yielded from my current R01, my other funded projects, as well as other data available at my institute. These goals stem directly from my funded projects and represent expansions in my current areas of expertise. Specifically, although I have the skill set needed to meet the genetic Aim of my current NIAAA R01 (AA020179 Stress- induced Drinking in OEF/OIF Veterans: the Role of Combat History and PTSD which is ongoing) I need increased training to fully utilize the data to ask new and deeper questions that are on the cutting edge of alcohol genetics research. Since my original training (in candidate gene designs) the field of genetics has changed significantly and increased in sophistication (e.g., genome wide association [GWAS] platforms, exom arrays, methylation arrays). These new platforms have introduced a number of analytic complexities, with multiple decision points in every stage of the process, from data cleaning to analysis to the interpretation of results. Thus, this K02 will give me the skills in the integration and harmonization of genomic data on multiple platforms (e.g., sequence, methylation, expression) to better utilize (beyond the original, now outdated aim) my NIAAA R01 data on the genomic influences on stress reactivity and subsequent alcohol use in soldiers. This aim will be achieved by hands-on training in molecular and epigenetics (including wetlab immersions), supervised statistical genetic analyses done in collaboration with leaders in the field, formal coursework and workshops, and individual tutoring by K02 consultants. Additionally, the K02 will deepen my expertise in the area of alcohol-related phenotypes, beyond stress-induced drinking, which has been the focus of my work to date. This aim will be achieved through directed readings, formal coursework, practical experience analyzing relevant datasets (e.g., NIAAA R37011408 A Longitudinal Study of Genes, Environment and Alcohol Misuse in College Students), and mentorship from leaders in the field (Dr. Kenneth Kendler). In summary, the overarching goal of the proposed K02 is to further my multidisciplinary independent program of research which aimed at the identification of risk and resilience factors, both biologic and psychosocial in nature, for traumatic stress related conditions (alcohol use disorders [AUDs], posttraumatic stress disorder [PTSD]) and translation of these findings into prevention and intervention programming. The K02 will provide me with protected time to fully engage in the training activities I have outlined, enabling me to coalesce my diverse training background and move my research program forward in ways not previously possible.