Statistical, population genetics and genetic epidemiology

统计、群体遗传学和遗传流行病学

• 批准号: 8734143
• 负责人: dmitri v zaykin
• 金额: $ 46.08万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8734143
• 关键词: Accounting; Affect; Alleles; Chronic; Clinical; Cohort Studies; Complex; Data; Data Set; Development; Disease; Disease susceptibility; Drowning; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Facial Pain; Freedom; Functional disorder; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Human; Human Genetics; Individual; Ligands; Linkage Disequilibrium; Maps; Mediating; Medicine; Methodology; Methods; Molecular; Molecular Profiling; Onset of illness; Pain; Pathway Analysis; Pathway interactions; Persons; Population Genetics; Predisposition; Process; Public Health; Reaction; Research; Risk; Role; Sampling; Serotonin Receptors 5-HT2; Shapes; Side; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism Map; Statistical Methods; Subgroup; Sum; T-Cell Receptor; T-Lymphocyte; Temporomandibular Joint Disorders; Testing; Tissue-Specific Gene Expression; Uncertainty; Weight; Work; base; case control; chronic pain; design; disorder prevention; genetic association; genetic epidemiology; genetic variant; health related quality of life; indexing; metabolomics; novel; receptor; response; statistics; trait

The genetic makeup of a person can be thought of as shaping their propensity to complex diseases, while environmental factors trigger onset of diseases and, together with genetic factors, can modify their progression. Research of my group reflects our continuing involvement in the design and analysis of large-scale genetic and genomic studies. We continue to devise methodology that is useful not only for genetic applications but also generally applicable for analysis of other kinds of multidimensional data where many statistical hypotheses are being evaluated, e.g. it is applicable in studies of epigenetic effects of exposures, in metabolomics studies, and in studies of differential gene expression. Our methods are designed to be general because they work off P‑values, which can result from various tests, including those accounting for environmental exposures and gene‑environment interactions. We have been extending collaborative aspects of our research, striving to bring modern statistical methodology to studies concerned with complex diseases and environmental exposures. In Slade et al (2013) we conducted a case-control genetic association study of relationships between 2925 SNPs and two subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD; and 2) TMD with widespread pain. Using our statistical extensions to pathway analysis we found that when compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway, while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway. A risk index representing combined effects of six SNPs from the serotonergic pathway was associated with greater odds of localized TMD, and the result was reproduced in a replication case-control cohort study. A risk index representing combined effects of eight SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain. The replicated association between serotonergic signaling and localized TMD represents a novel finding regarding etiology of chronic pain, while the observed association between T cell receptor pathway and TMD with widespread pain corroborates recent studies of the role of T cell-mediated mechanisms in pain. Common genetic variants usually contribute to molecular pathophysiological processes in ways that produce weak associations between individuals SNPs and clinical disease when assessed in human association studies. In this research, we distinguished phenotypically between biologically relevant subtypes of chronic TMD and applied a new analytic approach that searches for combinations of usually small genetic influences on known cellular signaling pathways. We found that anatomically localized and generalized pain represent clinically meaningful subgroups of TMD and that they have distinct molecular profiles with correspondingly-distinct genetic backgrounds. The results reveal a distinct role for serotonergic pathways in pathophysiology of TMD, although further work is needed to uncover the direction of this contribution. Potentially, this major cellular pathway contributing to development of localized TMD might be effectively treated using serotonin receptor 2 selective ligands. The TMD project prompted us to start looking into methodology for designs where the second (e.g. replication) part of the study can take advantage of effect directions observed in the primary study (Kuo et al., 2013). The primary study gives information about which allele at each SNP increases susceptibility to disease (i.e. the effect direction). Thus, for a particular individual in the replication sample, the number of susceptibility alleles can be added for each associated SNP, resulting in a single score. A statistic based on such a score would be independent of an association statistic used in the primary study, even though it borrows effect directions of the primary study, as long as the test utilized in the primary study is two-sided (i.e. oblivious to the effect direction). Therefore, association statistics of the primary and the secondary (e.g. replication) studies can be added (with weights reflecting the study sizes), and the distribution of the weighted sum can be determined. Our previous research suggests that careful pooling of summary statistics from different samples can be essentially as powerful as analysis based on individual-level data. Moreover, it is possible that in some situations, the test based on a combination the two statistics (from the primary and the secondary study) can be more powerful than a single test based on all data. Some reasons for this include incorporation of additional information that results from borrowing effect directions from the primary study and the fact that the score test in the secondary study is a single degree of freedom test. If all effect directions observed in the primary study were always correct, the secondary study test based on a single score would have had a remarkably high statistical power. However, due to statistical uncertainty, some effect directions may be incorrect. The variability in the number of correct determinations is also affected by linkage disequilibrium. Therefore, we investigated to what extent the power would be affected by these uncertainties. We also studied the problem of optimal allocation of subjects to the the primary and the secondary study with regard to power.

一个人的基因组成可以被认为是塑造他们对复杂疾病的倾向，而环境因素触发疾病的发作，并与遗传因素一起改变疾病的进展。我的团队的研究反映了我们持续参与大规模遗传和基因组研究的设计和分析。我们继续设计的方法，不仅是有用的遗传应用程序，但也普遍适用于其他类型的多维数据的分析，其中许多统计假设正在评估，例如，它是适用于暴露的表观遗传效应的研究，在代谢组学研究，并在差异基因表达的研究。我们的方法被设计为通用的，因为他们工作的P值，这可能会导致从各种测试，包括那些占环境暴露和基因环境相互作用。我们一直在扩大我们研究的合作方面，努力将现代统计方法引入与复杂疾病和环境暴露有关的研究。在Slade et al（2013）中，我们进行了一项病例对照遗传关联研究，研究了2925个SNP与常见的慢性面部疼痛病症颞下颌关节紊乱病（TMD）的两种亚型之间的关系：1）局限性TMD; 2）伴有广泛疼痛的TMD。使用我们的统计学扩展途径分析，我们发现，当与健康对照相比，与本地TMD的情况下，不同的SNP的等位基因频率映射到一个神经递质受体途径，而案件的TMD广泛的疼痛不同的SNP的等位基因频率映射到T细胞受体途径。一个风险指数代表的联合效应的6个单核苷酸单核苷酸途径与更大的几率局部TMD，并在一个复制病例对照队列研究中重现的结果。代表T细胞受体途径8个SNPs联合效应的风险指数与TMD伴广泛疼痛的可能性更大相关。β-胡萝卜素能信号传导和局部TMD之间的复制关联代表了关于慢性疼痛病因学的新发现，而T细胞受体途径和TMD与广泛疼痛之间观察到的关联证实了T细胞介导的机制在疼痛中的作用的最新研究。当在人类关联研究中评估时，常见的遗传变异通常以在个体SNP和临床疾病之间产生弱关联的方式促成分子病理生理过程。在这项研究中，我们区分了慢性TMD的生物学相关亚型之间的表型，并应用了一种新的分析方法，该方法搜索对已知细胞信号传导途径通常较小的遗传影响的组合。我们发现，解剖学定位和广义疼痛代表临床上有意义的亚组TMD，他们有不同的分子谱与相应的不同的遗传背景。结果揭示了一个独特的作用，在TMD的病理生理学中的β-胡萝卜素能途径，虽然需要进一步的工作，以揭示这种贡献的方向。潜在的，这一主要的细胞通路有助于发展本地TMD可能有效地治疗使用5-羟色胺受体2选择性配体。 TMD项目促使我们开始研究设计方法，其中研究的第二部分（例如复制）可以利用在主要研究中观察到的效果方向（Kuo等人，2013年）。初步研究提供了关于每个SNP的哪个等位基因增加对疾病的易感性的信息（即效应方向）。因此，对于复制样品中的特定个体，可以为每个相关SNP添加易感性等位基因的数量，从而产生单个评分。基于这种评分的统计量将独立于主要研究中使用的关联统计量，即使它借用了主要研究的效应方向，只要主要研究中使用的检验是双侧的（即忽略效应方向）。因此，可以添加主要和次要（例如，重复）研究的关联统计（权重反映研究大小），并可以确定加权和的分布。我们之前的研究表明，仔细汇集来自不同样本的汇总统计数据基本上与基于个人水平数据的分析一样强大。此外，在某些情况下，基于两种统计量（来自主要和次要研究）的组合的检验可能比基于所有数据的单一检验更有效。其原因包括纳入了主要研究中的借用效应方向所产生的额外信息，以及次要研究中的评分检验是单自由度检验。如果初级研究中观察到的所有效应方向始终正确，则基于单个分数的次级研究测试将具有非常高的统计功效。然而，由于统计的不确定性，一些影响方向可能是不正确的。正确测定数的变异性也受到连锁不平衡的影响。因此，我们研究了这些不确定性对功率的影响程度。我们还研究了关于权力的主题的最佳分配问题的小学和中学的研究。