Genome-wide association study of resilience

描述(由申请人提供)： 这项CDA-2申请提出了一个新颖的研究项目和严格的培训计划，以提供Aliza Wingo，M.D.，M.Sc。在分子遗传学方面受过尖端训练。Wingo博士建议对创伤相关的恢复力进行全基因组关联研究。从概念上讲，韧性是对不良心理后遗症的抵抗，尽管暴露在压力或创伤经历中。它有很大的遗传基础，遗传率在38%到71%之间，这表明遗传学研究很可能确定这种特征的重要原因。她的提议有三个具体目标。首先，她将在8000名平民受试者中进行恢复力GWAS，这些受试者的表型和基因型别正由格雷迪创伤项目收集，该项目由NIMH资助，并由她的主要导师指导。复原力将作为一种二分型和数量表型进行检验。接下来，她将在950名退伍军人中重复这项GWAS的重要发现。她的假设是，在平民人口中发现的弹性标记也与退伍军人人口中的弹性相关。最后，她将直接对至少30名退伍军人中与韧性有关的基因座进行测序，以确定韧性的罕见因果遗传变异。这个项目的结果将进一步加深我们对韧性的遗传基础的理解，这反过来又有助于加强保护因素的努力。 为严重的抑郁症、创伤后应激障碍或物质使用障碍寻找新的治疗或预防策略，这些疾病是美国退伍军人中最常见和致残的创伤相关精神病理学。对于培训目标，Wingo博士的目标是在群体遗传学方面获得坚实的基础，学习复杂的分析技术，使用全基因组和归属基因数据绘制复杂表型的关联图，并发展关于下一代测序研究设计和数据分析的知识和专业知识。为了实现这些培训目标，温戈博士将参加遗传学和统计学的课程，接受她的多学科指导团队的有组织的指导，并实施拟议的项目。Wingo博士有一个强大的多学科指导团队，包括Kerry Ressler医学博士(分子生物学、遗传学、神经科学和精神病学)、Bekh Bradley博士(心理学)、Michael Epstein博士(统计遗传学)和Timothy Read博士(人类遗传学)。埃默里大学的人类遗传学系是温戈博士的大部分基因训练的地方，在全国排名前十的遗传学系之一，提供了强大的训练环境。Wingo博士的长期目标是利用她作为精神病学家对精神病学表型的多方面了解，通过她的临床研究理学硕士获得的在流行病学和临床研究方面的坚实基础，以及拟议的尖端基因培训，成为精神病学和遗传学交界处的医生-科学家。她希望成为一名独立的研究员，并为我们理解韧性和其他精神障碍的遗传基础做出贡献。

DESCRIPTION (provided by applicant): This CDA-2 application proposes a novel research project and rigorous training plan to provide Aliza Wingo, M.D., M.Sc. with a cutting-edge training in molecular genetics. Dr. Wingo proposes to perform a genome-wide association study (GWAS) of trauma-related resilience. Conceptually, resilience is resistance to adverse psychological sequelae despite exposure to stressful or traumatic experiences. It has a substantial genetic basis with heritability ranging from 38% to 71%, suggesting that genetic studies are likely to identify important causes of this trait. Her proposal has three specific aims. First, she will perform a GWAS of resilience in 8000 civilian subjects, whose phenotypes and genotypes are being gathered by the Grady Trauma Project, funded by NIMH and directed by her primary mentor. Resilience will be examined both as a dichotomous and quantitative phenotype. Next, she will replicate the significant findings from this GWAS in 950 veterans. It is her hypothesis that the resilient markers identified in the civilian population are also associated with resilience in the veteran population. Finally, she wil directly sequence the loci that are associated with resilience in at least 30 veterans to identify rare causal genetic variants of resilience. Results from this project will further our understandin of the genetic basis of resilience, which in turn informs efforts in enhancing protective factors o finding novel treatments or prevention strategies for major depression, PTSD, or substance use disorders, some of the most common and disabling trauma-related psychopathology in U.S. veterans. For training goals, Dr. Wingo aims to acquire a strong foundation in population genetics, learn sophisticated analytical techniques for association mapping of complex phenotypes using genome-wide and imputation genotype data, and develop knowledge and expertise on next-generation sequencing study design and data analysis. To achieve these training goals, Dr. Wingo will attend courses on genetics and statistics, receive structured mentorship from her multidisciplinary mentoring team, and conduct the proposed project. Dr. Wingo has a strong multidisciplinary mentoring team, consisting of Kerry Ressler, M.D., Ph.D. (Molecular Biology, Genetics, Neuroscience, and Psychiatry), Bekh Bradley, Ph.D. (Psychology), Michael Epstein, Ph.D. (Statistical Genetics), and Timothy Read, Ph.D. (Human Genetics). The Human Genetics Department at Emory University, where most of Dr. Wingo's genetic training takes place, ranks in the top 10 genetic departments in the country and provides a strong training environment. Dr. Wingo's long-term goal is to capitalize on her multi-faceted understanding of psychiatric phenotypes as a psychiatrist, strong foundation in epidemiology and clinical research acquired through her Master of Science in Clinical Research, and the proposed cutting-edge genetic training to be a physician-scientist at the interface of psychiatry and genetics. She hopes to become an independent investigator and contribute to our understanding of the genetic basis of resilience and other psychiatric disorders.