The X-factor of complex disease: From population genetics to GWAS of Chromosome X

复杂疾病的X因素：从群体遗传学到X染色体的GWAS

• 批准号: 8501817
• 负责人: Alon Keinan
• 金额: $ 37.6万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501817
• 关键词: Accounting; Age of Onset; Alleles; Animal Model; Anus; Base Sequence; Chromosome Mapping; Communities; Complex; Computer software; Computing Methodologies; Data; Data Analyses; Data Set; Disease; Disease susceptibility; Dosage Compensation (Genetics); Duct (organ) structure; Etiology; Exhibits; Gender; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Health; Heritability; Human; Human Genetics; Investigation; Knowledge; Lead; Link; Maps; Mental Retardation; Methodology; Methods; Mission; National Human Genome Research Institute; Natural Selections; Outcome; Pathogenesis; Pattern; Phenotype; Play; Population; Population Analysis; Population Genetics; Predisposition; Procedures; Public Health; Quality Control; Quantitative Trait Loci; Recording of previous events; Research; Research Personnel; Rest; Risk; Role; Sampling; Severities; Sex Characteristics; Sex Chromosomes; Shapes; Solutions; Source; Staging; Statistical Methods; Stratification; Symptoms; Testing; United States National Institutes of Health; Variant; Work; X Chromosome; X Inactivation; analytical method; autosome; base; computerized data processing; computerized tools; design; disorder risk; gene interaction; genetic variant; genome wide association study; hexachlorocyclohexane x-factor; human disease; improved; innovation; insight; meetings; next generation; novel; programs; sex; sexual dimorphism; stem; trait

DESCRIPTION (provided by applicant): Chromosome X plays a distinctive and notable role in human health and disease, but there is a fundamental gap in studying its function in complex human disease, because the vast majority of genome-wide association studies (GWAS) disregarded or incorrectly analyzed X-linked data. Hence, there is an urgent need for methods that will enable investigation of the X-linked basis of complex diseases, especially those that exhibit gender disparity in risk, age of onset, severity, o symptoms. Such methods must account for differences between chromosome X and the rest of the genome, including differences in the modes of inheritance, sexual dimorphism in susceptibility, dosage compensation (X-inactivation), population genetic patterns, and ascertainment biases. The overarching long-term goal of the research program is to improve the search for sex-linked complex disease genes and to elucidate how evolutionary history has shaped human genetic variation differently on the sex chromosomes. The objective of this application is to discover X-linked loci underlying various complex diseases while putting forth improved statistical and computational methods and software that are specially designed for chromosome X. The underlying rationale is that the proposed research will help uncover a portion of the heritable basis of complex disease that has yet to be explained by GWAS loci ('missing heritability'), reveal the role of chromosome X in disease etiology, and advance the exploration of the sex-linked basis of sex-specific disease patterns. Guided by extensive preliminary data and analysis, this objective will be met by pursuing three specific aims: (1) Develop new statistical and computational methodologies to facilitate powerful association studies that accommodate chromosome X; (2) Discover and replicate X-linked disease genes in existing and emerging GWAS datasets spanning different diseases and populations; (3) develop a software package for X-linked association studies. The innovation of the proposed research stems from the novel analytical methodologies that accurately deal with the challenges surrounding the analysis of chromosome X. Its contribution will be significant because it will bring chromosome X-which has so far been largely omitted-into the GWAS landscape and, specifically, will find novel X-linked associations underlying complex human disease while making analytical methods available for the next generation of association studies. This contribution will be further multiplied by offering a software package implementing all methods to the scientific community, thus allowing researchers to uncover X-linked genes underlying additional complex diseases and in additional populations. Collectively, the proposed research is significant as it will substantially advance our understanding of the role chromosome X plays in complex human disease.

描述（由申请人提供）： X染色体在人类健康和疾病中发挥着独特而显着的作用，但在研究其在复杂人类疾病中的功能方面存在根本性差距，因为绝大多数全基因组关联研究（GWAS）忽视或错误地分析了X连锁数据。因此，迫切需要能够调查复杂疾病的 X 连锁基础的方法，特别是那些在风险、发病年龄、严重程度或症状方面表现出性别差异的疾病。这些方法必须考虑 X 染色体和基因组其余部分之间的差异，包括遗传模式的差异、易感性的性别二态性、剂量补偿（X 失活）、群体遗传模式和确定偏差。该研究计划的总体长期目标是改进对与性别相关的复杂疾病基因的搜索，并阐明进化历史如何在性染色体上以不同的方式塑造人类遗传变异。该应用的目的是发现各种复杂疾病背后的 X 连锁基因座，同时提出专门为 X 染色体设计的改进的统计和计算方法以及软件。其基本原理是，拟议的研究将有助于揭示部分可遗传的基因。尚未通过 GWAS 位点（“缺失遗传性”）解释的复杂疾病的基础，揭示 X 染色体在疾病病因学中的作用，并推进对性别特异性疾病模式的性别相关基础的探索。在广泛的初步数据和分析的指导下，这一目标将通过追求三个具体目标来实现：（1）开发新的统计和计算方法，以促进适应X染色体的强大关联研究； (2) 在涵盖不同疾病和人群的现有和新兴 GWAS 数据集中发现和复制 X 连锁疾病基因； (3)开发X连锁关联研究软件包。拟议研究的创新源于新的分析方法，可以准确地应对 X 染色体分析的挑战。它的贡献将是重大的，因为它将把迄今为止基本上被忽略的 X 染色体带入 GWAS 领域，并且具体来说，将发现复杂人类疾病背后的新型 X 连锁关联，同时为下一代关联研究提供分析方法。通过向科学界提供实施所有方法的软件包，这一贡献将进一步倍增，从而使研究人员能够发现更多复杂疾病和更多人群中潜在的 X 连锁基因。总的来说，这项研究意义重大，因为它将极大地增进我们对 X 染色体在复杂人类疾病中所扮演的角色的理解。