Evolutionary Roles of Homozygosity & Copy Number Variation in Mental Disorders

描述（由申请人提供）：这个指导研究科学家发展奖的目的是建立马修凯勒博士作为一个独立的研究精神病遗传学。该应用程序汇集了进化遗传学，统计遗传学和精神病学的进展，以建立一个跨学科的研究计划，以了解精神疾病的遗传变异。具体而言，培训和研究的重点是拷贝数变异（CNVs）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。进化遗传学有助于在丰富的概念框架内解释发现，将它们与深刻的文献联系起来，并提出几个关键假设。 培训的目标是培养启动独立资助的跨学科研究事业所需的技能。培训内容包括：（1）来自三位导师和四位顾问的直接合作和培训，他们是该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;（3）参加研讨会和会议，涵盖基因组数据分析，精神病学遗传学和进化遗传学;（4）教学课程和指导研究生;以及（5）撰写R 01申请的指导。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CNVs和EH如何与精神分裂症和重度抑郁症相关。研究CNVs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。这项研究有可能进一步了解精神障碍的进化，导致有关导致其风险的分子机制的具体数据，并提出未来研究的具体途径。 公共卫生相关性：拟议的项目应增加对精神分裂症和重性抑郁症的分子遗传和进化理解，澄清罕见变异与常见变异在多大程度上导致其风险，从而进行随访（例如，重测序）研究重要的基因组区域，并可能为旨在开发与基因剂量相关的诊断测试和治疗的转化研究提供信息。

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.