Cognitive Endophenotypes for Genetic Studies of Alzheimer's Disease

描述(由申请人提供)：在这份K01申请中，凯瑟琳·海登博士正在寻求遗传学方面的培训，目的是探索阿尔茨海默病(AD)的认知内表型(代表潜在疾病基因型的潜在或亚临床表型)，为正在进行的和未来的遗传学研究提供信息。该项目建立在候选人先前工作的基础上，重点是提供遗传学领域的高级专业知识，以促进她作为独立研究人员的发展。该计划利用了布莱恩阿尔茨海默病研究中心(Bryan ADRC)及其合作伙伴、杜克大学基因组科学与政策研究所(IGSP)、老龄化研究中心以及生物统计和生物信息学系的研究环境和充足的资源。这项应用的研究计划集中在推进方法学，以加强对涉及AD的尚未确定的风险基因的检测。这项申请建议使用来自NIH资助的四项大型研究的样本，这些研究在临床数据收集方法上都已得到协调(缓存县记忆研究、Bryan ADRC队列、NAS-NRC双胞胎研究和老年抑郁症的神经认知结果研究)，使用假设驱动和基于经验的统计方法严格确定AD的内表型。在导师凯瑟琳·威尔什-博默(Bryan ADRC&CCMS Pi)和David Goldstein(人口基因组学与药物遗传学IGSP主管)的指导下，候选人的职业发展计划还将受益于合作者Carl Pieper(生物统计学)、Brenda Plassman(双胞胎研究)和David Steffens(老年性抑郁症)的投入，因为她努力理解和开发独特队列中的潜在模型：培训计划包括潜在类分析、潜在类轨迹、遗传学和计算生物学的课程，以及神经心理学方法、遗传研究设计和遗传方法独特的统计方法方面的经验性培训。这一相关和及时的应用解决了将内表型分析方法应用于群体基因工作的需要。最终，AD内表型的应用将有助于识别新的基因，突出潜在的致病途径，并为未来的治疗开发提供途径。

DESCRIPTION (provided by applicant): In this K01 application, Kathleen Hayden PhD is seeking training in genetics with a goal of exploring cognitive endophenotypes (latent or sub-clinical phenotypes representing the underlying disease genotype) of Alzheimer disease (AD) to inform ongoing and future genetic studies. The project builds on the candidate's prior work and is focused on providing advanced expertise in the area of genetics in order to facilitate her development as an independent researcher. The plan leverages the research environment and ample resources of the Bryan Alzheimer's Disease Research Center (Bryan ADRC) and its partners, the Duke Institute for Genome Sciences and Policy (IGSP), the Center for the Study of Aging, and the Department of Biostatistics and Bioinformatics. The research plan in this application is focused on advancing methodology to enhance the detection of yet to be determined risk genes involved in AD. This application proposes to use samples from four large NIH funded studies which have all been harmonized in their clinical data collection methodologies (Cache County Memory Study, Bryan ADRC cohorts, NAS-NRC Twin Study, and the Neurocognitive Outcomes of Depression in the Elderly Study) to rigorously determine AD endophenotypes using hypothesis driven and empirically based statistical approaches. Guided by Mentors, Kathleen Welsh-Bohmer (Bryan ADRC & CCMS PI) and David Goldstein (Director of Population Genomics & Pharmacogenetics IGSP) the candidate's career development plan will also benefit from the input of collaborators Carl Pieper (biostatistics), Brenda Plassman (twin studies), and David Steffens (geriatric depression) as she strives to understand and develop latent models within the unique cohorts: The training program includes coursework in latent class analysis, latent class trajectories, genetics, and computational biology as well as experiential training in neuropsychological methods, genetic study design, and statistical approaches unique to genetic methodologies. This relevant and timely application addresses a need to apply endophenotyping methods to population genetic work. Ultimately the application of endophenotypes of AD will facilitate the identification of new genes, highlight potential causal pathways of disease, and suggest avenues for future treatment development.