Evolutionary Roles of Homozygosity & Copy Number Variation in Mental Disorders

描述(由申请者提供)：这个指导研究科学家发展奖的目标是建立马修·凯勒博士作为精神病学遗传学的独立研究员。该应用程序结合了进化遗传学、统计遗传学和精神病学的进步，建立了一个跨学科的研究计划，以了解精神障碍背后的遗传变异。具体地说，培训和研究的重点是拷贝数变异(CNV)和扩展纯合性(EH)如何影响精神障碍风险。将这种变异与精神障碍联系起来的努力才刚刚开始，因此有可能对这一研究领域做出重要贡献。进化遗传学有助于将发现置于丰富的概念框架内，将它们与深入的文献联系起来，并提出几个批判性假设。培训的目标是发展所需的技能，以启动独立资助的跨学科研究事业。培训包括：(1)三名导师和四名顾问的直接协作和培训，他们是这一应用程序核心方面的领导者；(2)生物信息学、统计遗传学、精神病学和进化遗传学的课程工作；(3)参加涵盖基因组数据分析、精神病学遗传学和进化遗传学的研讨会和会议；(4)教学课程和指导研究生；以及(5)编写R01应用程序的指导。行为遗传学研究所为实现这一培训提供了丰富的智力环境。该研究项目将使用来自多个来源的全基因组SNP数据来研究CNV和EH与精神分裂症和严重抑郁症的关系。研究CNV和EH可以评估常见和罕见的遗传变异。这本身就很重要，但也可以为精神障碍的进化史和影响它们的基因提供重要线索。这项研究有可能促进对精神障碍的进化理解，导致关于导致其风险的分子机制的具体数据，并建议未来研究的具体途径。 公共卫生相关性：拟议的项目应该增加对精神分裂症和严重抑郁症的分子遗传和进化的理解，澄清罕见和常见变异对其风险的影响程度，导致对重要基因组区域的后续研究(例如，重新测序)，并可能为旨在开发与基因剂量相关的诊断测试和治疗的翻译研究提供信息。

DESCRIPTION (provided by applicant): The objective of this Mentored Research Scientist Development Award is to establish Dr. Matthew Keller as an independent investigator in psychiatric genetics. The application brings together advances from evolutionary genetics, statistical genetics, and psychiatry to build an interdisciplinary research program for understanding the genetic variation underlying mental disorders. Specifically, training and research focus on how copy number variants (CNVs) and extended homozygosity (EH) influence mental disorder risk. Efforts to link such variation to mental disorders are just beginning, and so there is a potential for making important contributions to this area of inquiry. Evolutionary genetics helps situate findings within a rich conceptual framework, linking them to a deep literature and suggesting several critical hypotheses. The training goal is to develop the skills needed to launch an independently funded, interdisciplinary research career. The training includes: (1) direct collaboration and training from three mentors and four consultants who are leaders in core aspects of this application; (2) coursework in bioinformatics, statistical genetics, psychiatry, and evolutionary genetics; (3) attendance at workshops and conferences covering analysis of genomic data, psychiatric genetics, and evolutionary genetics; (4) teaching courses and mentoring graduate students; and (5) guidance in writing an R01 application. The Institute for Behavioral Genetics offers rich intellectual environments for achieving this training. The research project will use whole genome SNP data from several sources to examine how CNVs and EH are related to schizophrenia and major depression. Studying CNVs and EH allows assessment of common as well as rare genetic variants. This is important in its own right, but also can provide important clues to the evolutionary history of mental disorders and the genes affecting them. This research has the potential to further the evolutionary understanding of mental disorders, lead to concrete data on the molecular mechanisms that contribute to their risk, and suggest specific avenues of future research. PUBLIC HEALTH RELEVANCE: The proposed project should increase the molecular genetic and evolutionary understanding of schizophrenia and major depression, clarifying the degree to which rare versus common variants account for their risk, leading to follow-up (e.g., resequencing) investigations of important genomic regions, and potentially informing translational research aimed at developing diagnostic tests and treatments related to gene dosage.