Genes, early adversity, and sensitive periods in social-emotional development

描述（由申请人提供）：该指导研究科学家职业发展奖（K01）将为候选人提供必要的技能和知识，以开发一个独立的研究项目，使用流行病学方法确定精神疾病的遗传和环境决定因素。虽然精神症状和障碍，如抑郁和焦虑，具有复杂的病因，并通过基因、经历及其相互作用（例如，基因-环境相互作用；GxE）的影响而出现，但确定GxE相互作用的努力取得了不同程度的成功。当前提案的总体目标是测试GxE效应在发育的“敏感时期”或生命周期中的时间窗口最强的假设，此时发育中的人类大脑对经历特别脆弱或敏感，包括暴露于社会逆境（例如，儿童虐待，社会剥夺）。这一主要假设将在三个方面得到验证。目的1将研究逆境暴露时间对情绪识别技能和随后内化症状发展的影响。目的2将研究“敏感期相关基因通路”的遗传变异对情绪识别技能和内化症状的影响。敏感期相关的基因通路将由两组基因定义。第一个将是在nimh资助的脑云资源（一个人类前额皮质基因表达的时间模式数据库）中识别的基因集。在这组基因中选择的基因将在生命的早期高度和差异表达。第二组基因将是在动物研究中显示的调节敏感期时间的基因的人类同源基因（即gad2， otx2, rtnf， lynx1和bdnf）。snp将被映射到a

DESCRIPTION (provided by applicant): 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).