Genome-wide Haplotype Association Analysis in Mental Disorders

描述（由申请人提供）：精神分裂症、抑郁症等精神疾病是一种复杂的疾病，其易感性、发展和治疗反应受复杂的遗传和环境因素的调节。了解这些疾病的遗传学可以为这些疾病的诊断、发病机制和治疗方法的发展提供重要的见解。随着综合基因组信息和经济高效的基因分型技术的发展，全基因组关联研究（GWAS）已成为确定复杂疾病的中等遗传决定因素的一种有前途的新工具。然而，精神疾病的GWAS还没有带来明确的发现。检测小效应基因的能力不足和无法纳入复杂的相互作用是缺乏可复制发现的两个主要原因。为了确保GWAS的进一步成功，需要先进的分析工具和战略来解决这些问题。这一建议旨在针对这一需要制定方法。我们的长期目标是提高复杂多标记分析的有效性，并最终促进研究设计和标记选择。建模多标记多态性提供了最大数量的基因组信息，复杂的统计建模允许仔细和集体考虑潜在的遗传和环境因素。在本文中，我们将重点放在基于模型的单倍型分析上，并提出了一个两阶段的框架来检测和理解GWAS中的关联信号。第一阶段的目标是有效地筛选出具有全局单倍型-性状关联的区域。第二阶段的重点是对单倍型效应的特定模式进行更系统的检查。受研究人员在合作工作中出现的问题的激励，我们的方法发展的中心考虑包括：(a)单倍型信息的有效利用，(b)基于回归的框架的制定，(c)检测主要和相互作用效应的能力，(d)从最初的全球筛选到后续的具体评估的系统推断过程，以及(e)建立坚实的理论基础并在用户友好的软件中进行稳健的实施。我们将通过以下三个具体目标来实现我们的目标：(1)开发基于回归的单倍型相似性方法，用于检测表现出遗传主效应和/或相互作用效应的区域；(2)开发一种惩罚似然回归方法，用于表征识别区域内具有显著主效应和/或相互作用效应的单倍型；(3)将目标(1)和(2)中的方法应用于精神障碍的协作GWAS，用于方法评估和疾病基因检测。开发和分发供公众使用的计算机程序。

DESCRIPTION (provided by applicant): Mental diseases such as schizophrenia and depression are complex diseases for which susceptibility, development and treatment response are mediated by intricate genetic and environmental factors. Understanding the genetics of these diseases can illuminate significant insights into the development of diagnostics, pathogenesis and therapeutics of these diseases. With recent advancements in comprehensive genomic information and cost-effective genotyping technologies, genome-wide association studies (GWAS) have become a promising new tool for identifying modest genetic determinants of complex disorders. However, GWAS for psychiatric disorders have yet to bring definitive findings. Insufficient power to detect small-effect genes and inability to incorporate complex interactions are the two major attributes for lack of replicable findings. To ensure further success of GWAS, advanced analytical tools and strategies are needed to resolve these issues. This proposal intends to develop methodology in response to this need. Our long-term goal is to advance the efficacy of complex multimarker analysis and eventually to facilitate study design and marker selection. Modeling multimarker polymorphisms provides maximal amount of genomic information, and complex statistical modeling allows careful and collective consideration of potential genetic and environmental factors. In this proposal we focus on model-based haplotype analysis, and propose a two-stage framework to detect and to comprehend the association signals in GWAS. The first stage aims to effectively screen out regions with global haplotype-trait association. The second stage focuses on a more systematic examination of the specific patterns of haplotype effects. Motivated by issues arising in the collaborative works by the investigators, the central considerations of our methodology development include: (a) the efficient usage of haplotype information, (b) the formulation of regression-based framework, (c) the capacity to detect main and interaction effects, (d) a systematic inference progression from initial global screening to follow-up specific evaluation, and (e) the establishment of a solid theoretical foundation and robust implementation in user-friendly software. We will achieve our objectives through the following three specific aims: (1) to develop regression-based haplotype-similarity methods for detecting regions that exhibit genetic main and/or interaction effects, (2) to develop a penalized-likelihood regression approach for characterizing haplotypes of significant main and/or interaction effects within the identified regions, and (3) to apply the methods from aims (1) and (2) to the collaborative GWAS of mental disorders for method evaluation and disease gene detection, and to develop and distribute computer programs for public use. PUBLIC HEALTH RELEVANCE: Completion of the proposed work will provide effective statistical tools for a new process of studying the genetic etiology of complex diseases, from initial genome screening to subsequent explanatory examination. These tools can facilitate scientists' understanding of complex diseases and eventually lead to better design of prevention, detection and treatment strategies to improve human health.