This Mentored Research Scientist Career Development Award (K01) will provide the candidate with the necessary skills and knowledge to develop an independent program of research that uses epidemiological methods to identify genetic and environmental determinants of psychiatric disorders. Although psychiatric symptoms and disorders, such as depression and anxiety, have a complex etiology and emerge through the effect of genes, experience, and their interaction (e.g., gene-environment interaction; GxE), efforts to identify GxE interactions have had mixed success. The overall aim of the current proposal is to test the hypothesis that GxE effects are strongest during sensitive periods in development, or windows of time in the lifespan when the developing human brain is particularly vulnerable or sensitive to experience, including exposure to social adversity (e.g., child maltreatment, social deprivation). This main hypothesis will be tested in three aims.
Aim 1 will examine the effect of timing of exposure to adversity on emotion recognition skills and subsequent development of internalizing symptoms.
Aim 2 will examine the effect of genetic variation in sensitive period relevant gene pathways on emotion recognition skills and internalizing symptoms. Sensitive period relevant gene pathways will be defined by two sets of genes. The first will be sets of genes identified in the NIMH-funded Brain Cloud resource, a database of temporal patterns of gene expression in the human prefrontal cortex. Genes selected in this gene set will be highly and differentially expressed in the early years of life. Te second gene set will be the human orthologues of genes shown in animal studies to regulate the timing of sensitive periods (i.e., gad2, otx2, rtnf, lynx1, and bdnf). SNPs will be mapped to a gene using ProxyGeneLD. All SNPs in the pathway will be modeled simultaneously; thus no SNP-level tests will be conducted.
Aim 3 will investigate gene-by adversity interactions (GxE), focusing on whether genetic variation in sensitive period relevant gene pathways modifies the association between timing of adversity and both emotion recognition and internalizing symptoms. Findings generated from the proposed research can help identify periods in the lifespan when interventions could be most effective in preventing internalizing symptoms, mechanisms by which adversity increases risk for psychopathology, and possible targets to treat internalizing symptoms and disorders. The training component of the proposed award, centered in the Psychiatric and Neurodevelopmental Genetics Unit at the Massachusetts General Hospital, is designed to provide the candidate with the skills and knowledge necessary to reach her career goals and complete the K01 research aims. The candidate, Dr. Erin C. Dunn, has a background in social and psychiatric epidemiology, but no training in the use of bioinformatics tools, large-scale genomic data, and mechanisms linking exposure to adversity to subsequent risk for internalizing symptoms. Her long-term career goal is to become an independent, translational epidemiologist, with the skills and knowledge to translate findings from basic science research and improve population-level health. To accomplish this goal, Dr. Dunn will be trained in two novel areas: (1) genomic and bioinformatics tools for epidemiology; and (2) developmental neuroscience of psychopathology. Within these training areas, Dr. Dunn will develop the skills to use bioinformatics resources, conduct pathway and gene set analyses, and identify patterns of gene expression. These newly-acquired skills will be integrated with conceptual and methodological strategies to identify sensitive periods in development and the pathways through which exposure to adversity increases risk for psychopathology. Training activities include coursework, workshops, conference attendance, as well as supervised research projects, individual training, and ongoing supervision and consultation. Training will be overseen by two internationally recognized mentors (Dr. Jordan Smoller and Dr. Charles Nelson) and a panel of expert consultants. This interdisciplinary mentorship and consultant team is comprised of experts in molecular and statistical genetics, gene expression, bioinformatics, developmental neuroscience, GxE, and psychiatric disorders. The training aims will be applied in the research component of the award. The research component consists of two studies designed by Drs. Dunn, Smoller, and Nelson to test the hypotheses linked to the aims noted above. The studies use data from the two largest, individually- genotyped general population datasets in the world, in which internalizing symptoms, emotion regulation skills, and exposure to adversity have been deeply phenotyped from early childhood through adolescence. These studies are: the Avon Longitudinal Study of Parents and Children (n=13,988) and the Generation R study (n=9,745). Together, these training and research projects will constitute the basis for an R01 proposal that Dr. Dunn will prepare in the third year of the award period. This R01 will employ the training and research completed during the award period and will seek to replicate and extend findings that support a GxE informed model to identify sensitive periods. Depending on the K01 results, such a model could include specific gene sets, measures of emotion recognition skills and other social competencies, timing of adversity, and measures of depression, anxiety, and internalizing symptoms. It could also include other factors that mitigate or reverse the effects of exposure to adversity during the sensitive period (e.g., fetal drug exposure).
The proposed project examines the etiologic relationship between genes, exposure to adversity, and their interaction (i.e., gene-environment interaction; GxE) on emotion recognition skills and subsequent development of internalizing symptoms in children and adolescents. Findings generated from this research will help identify sensitive periods in development, or times in the lifespan when the effects of adversities are most harmful. The identification of sensitive periods in development will aid in determining mechanisms through which adversity increases risk for psychopathology and will help guide the investment of public health resources to when they can have the highest impact on reducing risk for mental disorder.
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