Statistical Genetics Methods for Mixed Pathologies

描述(由申请者提供)：这份有指导的职业发展补助金申请提出了一项培训计划，将Fardo博士之前在生物统计学和统计遗传学方面的研究整合到包括高度流行的神经退行性疾病在内的老龄化疾病的研究中。他的长期职业目标是开发一个独立的研究计划，专注于统计方法的进步，以了解复杂疾病背后的遗传学，重点是大脑老化疾病。将通过以下方式实现这一目标：通过正规课程和辅导经验获取老龄脑部疾病领域的知识；相关研究数据的管理、分析和解释方面的培训；全面审查老龄研究中使用的大规模遗传数据以及新的尖端生物统计方法可改进分析的领域；应用、改进和发展遗传统计方法来分析这一大规模遗传数据；以及继续进行负责任的研究培训。法尔多博士的研究培训将包括一支热情的跨学科研究人员团队，他们在研究方面有着良好的记录。这项K25应用的总体目标是利用大型、多中心衍生数据库提供的临床和神经病理学数据，以确定与特定神经病理内表型相关的单核苷酸多态(SNP)。大多数研究年龄相关的复杂疾病的遗传易感性的研究都是通过直接比较有或没有疾病的人的模型来概念化的，例如，有或没有阿尔茨海默病(AD)。然而，这种疾病/非疾病的方法是低效的，不适合于研究所谓的混合病理的遗传危险因素，这些混合病理是老年人的常态。拟议的研究计划将询问大量尸检大脑的遗传与神经病理特征的相关性。这将通过利用数据完成 收集自美国国立卫生研究院资助的大型资源。神经病理学数据和全基因组遗传数据将从这些资源中合并，并将全面测试混合病理性痴呆和神经病理特征的遗传相关性。这项工作将导致新的方法来分析混合病理痴呆和神经病理特征，以及探索相关的遗传危险因素和基因-环境相互作用。

DESCRIPTION (provided by applicant): This mentored career development grant application proposes a training program to integrate Dr. Fardo's previous research in biostatistics and statistical genetics into investigations of aging disorders including highly prevalent neurodegenerative diseases. His long-term career goal is to develop an independent research program focusing on the advancement of statistical methodologies to understand the genetics underlying complex diseases, with an emphasis on diseases of brain aging. This will be achieved through acquiring knowledge in the area of brain diseases of aging through formal coursework and mentored experiences; training in the management, analysis and interpretation of associated research data; comprehensive examination of the large-scale genetic data used in aging studies and the areas where novel, cutting-edge biostatistical methodologies could improve analyses; application, refinement and development of statistical genetic approaches to the analysis of this large-scale genetic data; and the continuation of training in the responsible conduct of research. Dr. Fardo's research training will involve an enthusiastic team of cross- disciplinary researchers with a strong research track record. An overall goal of this K25 application is to capitalize on the clinical and neuropathologic data available from large, multicenter-derived databases to identify single nucleotide polymorphisms (SNPs) associated with specific neuropathologic endophenotypes. Most research investigating the genetic predisposition of age-related complex diseases has been conceptualized with a model directly comparing those with or without a disease, for example, with or without Alzheimer's disease (AD). However, this disease/non-disease approach is inefficient and not appropriate for investigating the genetic risk factors for so-called mixed pathologies which are the norm in advanced age. The proposed research program will interrogate genetic associations with neuropathologic features of a large cohort of autopsied brains. This will be done by utilizing data collected from large, NIH-funded resources. Neuropathology data and genome-wide genetic data will be merged from these resources, and genetic associations for mixed-pathology dementias and neuropathologic features will be comprehensively tested. This work will result in new methods to analyze mixed-pathology dementias and neuropathologic features as well as the exploration of associated genetic risk factors and gene-environment interactions.