The X-factor of complex disease: Development, implementation, and extensive application of methods for analysis of the X chromosome in GWA, sequence-based association, and eQTL studies

复杂疾病的 X 因素：GWA、基于序列的关联和 eQTL 研究中 X 染色体分析方法的开发、实施和广泛应用

• 批准号: 9548718
• 负责人: ANDREW G CLARK
• 金额: $ 37.74万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548718
• 关键词: Address; Animal Model; Autoimmune Diseases; Base Sequence; Biological; Cardiovascular Diseases; Cause of Death; Cognition; Communities; Complex; Computer software; Computing Methodologies; Coronary Arteriosclerosis; Custom; DNase I hypersensitive sites sequencing; Data; Data Analyses; Deoxyribonuclease I; Development; Disease; Disease susceptibility; Etiology; Factor X; Funding; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Health; Human; Human Genetics; Human Genome; Hypersensitivity; Imagery; Individual; Investigation; Light; Link; Linkage Disequilibrium; Lipids; Malignant Neoplasms; Medical Genetics; Mendelian disorder; Mental disorders; Meta-Analysis; Methodology; Methods; Mission; Moods; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; Natural Selections; Outcome; Pathogenesis; Pathway interactions; Pattern; Perception; Pharmacogenetics; Phase; Play; Population Genetics; Prevalence; Public Health; Quantitative Trait Loci; Recording of previous events; Regulatory Element; Research; Review Literature; Risk Factors; Role; Site; Statistical Methods; Symptoms; Testing; United States National Institutes of Health; Work; X Chromosome; X Inactivation; analytical method; base; computerized data processing; disability; disease diagnosis; disorder risk; epigenetic marker; exhaustion; experience; experimental study; gene function; gene interaction; genome wide association study; genome-wide analysis; hexachlorocyclohexane x-factor; identity by descent; improved; innovation; insight; method development; nervous system disorder; novel; novel strategies; open source; programs; rare variant; risk variant; sex; sexual dimorphism; software development; stem; study population; tool; trait; trend

7. PROJECT SUMMARY/ABSTRACT In the historical endeavor striving to understand complex disease via genome-wide association studies (GWAS), the X chromosome (X) has typically been disregarded or incorrectly analyzed due to analytical complications stemming from its unique mode of inheritance and population genetic patterns. This trend has carried over into sequence-based association studies, genome-wide studies of regulatory elements, and studies of gene expression. Beyond comprising 5% of the human genome, X likely contributes to the sex- specific prevalence, symptoms or progression observed in most complex diseases. These include many leading causes of death and disability, such as neurological and psychiatric disorders, cardiovascular diseases, autoimmune diseases, and cancer. This project will support the applicant’s long-term goal of advancing the search for X-linked complex disease genes while elucidating how evolutionary history and natural selection uniquely shaped human genetic variation on X. The objectives of this application are the development of methods and software for analyzing X in GWAS and sequence-based association studies, and their application for discovering X many risk loci underlying complex diseases. The rationale for performing this work is that it will reveal the role of X in the etiology of several diseases, and advance the exploration of sexual dimorphism in disease. This will be achieved by pursuing the following specific aims: 1) Develop new X-specific statistical and computational methods for X-wide association studies (XWAS), expression quantitative trait loci (eQTL) studies of X, and sex-specific, X-tailored analysis of DNase-seq experiments; 2) Facilitate accurate genotype calling and processing of X in sequence data, and develop X-optimized tests for rare variant association studies and identity-by-descent mapping; 3) Discover, replicate, and interpret X-linked associations, based on analysis and meta-analysis of data from hundreds of studies, with a focus on common psychiatric disorders, quantitative risk factors of coronary artery disease, and eQTL; 4) Develop open source, freely available software that implements all methods from Aim 1 and Aim 2, together with existing methods. The proposed research is innovative in that it will develop new approaches and methodologies to accurately analyze X, pioneering the inclusion of X in association studies and related fields. Its contribution will be novel statistical and computational methods tailored specifically for X, and insight into the role of X in several complex diseases and traits. The contribution will be further increased by the availability of software that facilitates analysis by others of the thousands of studies where X remains essentially unexplored. Overall, the proposed research is significant, and relevant to public health, because it will help reveal the role of X in human complex disease etiology, and help advance sex-specific disease diagnosis and treatment.

7。项目摘要/摘要 在历史努力中，通过全基因组关联研究来理解复杂疾病 （GWAS），X染色体（X）通常因分析而被忽略或错误地分析 源自其独特的遗传和人口遗传模式的并发症。这个趋势有 延续到基于序列的关联研究，调节元素的全基因组研究以及 基因表达的研究。除了完成5％的人类基因组外，X可能有助于性别 - 在大多数复杂疾病中观察到的特异性患病率，症状或进展。这些包括许多 死亡和残疾的主要原因，例如神经和精神疾病，心血管疾病， 自身免疫性疾病和癌症。该项目将支持申请人的长期目标 搜索X连锁的复杂疾病基因，同时阐明如何进化史和自然选择 X上具有独特形状的人类遗传变异。该应用的目的是发展 GWAS和基于序列的关联研究中的分析X方法和软件及其应用 用于发现X许多风险基因座基础复杂疾病。执行这项工作的理由是 将揭示X在多种疾病的病因中的作用，并推进对性二态性的探索 在疾病中。这将通过追求以下特定目的来实现：1）开发新的X特定统计数据 X宽关联研究（XWAS）的计算方法，表达定量性状位置（EQTL） DNase-Seq实验的X和性别特异性X级分析的研究； 2）促进准确的基因型 在序列数据中调用和处理X，并为罕见变体关联开发X优化测试 研究和逐渐绘制的映射； 3）基于 对数百项研究的数据分析和荟萃分析，重点是常见的精神疾病， 冠状动脉疾病和EQTL的定量危险因素； 4）开发开源，免费可用 从AIM 1和AIM 2中实现所有方法的软件以及现有方法。提议 研究具有创新性，因为它将开发新的方法和方法来准确分析X， 开创X在关联研究和相关领域中的包含。它的贡献将是新颖的统计数据 和专门针对X的计算方法，并深入了解X在几种复杂疾病中的作用 和特质。通过可用的软件可用性，可以进一步提高贡献 成千上万的研究中的其他研究本质上仍然是意外的。总体而言，拟议的研究是 与公共卫生有关，因为它将有助于揭示X在人类复杂疾病中的作用 病因，并有助于提高性别特异性疾病的诊断和治疗。