Polygenic risk scores and health disparities: the role of blood cells immune response and evolutionary adaptation

多基因风险评分和健康差异：血细胞免疫反应和进化适应的作用

• 批准号: 10212768
• 负责人: Nancy J Cox
• 金额: $ 99.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212768
• 关键词: APOL1 gene; Accounting; Affect; African American; Alleles; Asian Americans; Asians; Biological Assay; Biological Markers; Biology; Blood Cells; Blood Platelets; C-reactive protein; Calibration; Chronic; Chronic Disease; Clinical; Communicable Diseases; DNA; Data; Data Set; Diagnosis; Disease; Disease Pathway; Disease Progression; Disease susceptibility; Erythrocytes; European; Fibrin fragment D; Fibrinogen; Frequencies; Gene Frequency; Genetic Variation; Genome; Genotype; Goals; Health; Healthcare; Hematology; Heritability; Hispanics; Immune; Immune response; Individual; Inflammation; Inflammatory; Jackson Heart Study; Joints; Kidney; Laboratories; Latino; Lead; Leukocytes; Linkage Disequilibrium; Measures; Mendelian disorder; Modeling; Monitor; Mutation; Native American Ancestry; Natural Selections; Outcome; Pathway interactions; Performance; Phenotype; Population; Population Genetics; Population Heterogeneity; Population Sizes; Property; Research Methodology; Risk Estimate; Role; Sample Size; Scoring Method; Sickle Cell Anemia; Sickle Hemoglobin; Site; Structure; Susceptibility Gene; Testing; Variant; Weight; White Blood Cell Count procedure; Women' s Health; base; chemokine receptor; clinical biomarkers; clinical care; cohort; data harmonization; diagnostic accuracy; disorder risk; endophenotype; genetic variant; genome wide association study; health care delivery; health care service utilization; health disparity; human disease; improved; in silico; inter-individual variation; lifetime risk; method development; novel; pathogen; personalized medicine; phenotypic data; polygenic risk score; predictive modeling; pressure; risk variant; thrombotic; trait

Abstract The large number of disease susceptibility loci identified from genome-wide association studies (GWAS) is enabling polygenic risk scores (PRS) to deliver on their promise to improve health outcomes and to transform the practice of personalized medicine. The reduced quality of PRS for common diseases and related quantitative traits for populations of recent African, Asian, and Native American ancestries relative to those for populations of recent European ancestries, however, threatens to create a new class of disparities in the delivery of healthcare based on PRS. The number of individuals of non-European ancestry with genome interrogation are growing much more rapidly now than 5 years ago; nevertheless, the number of individuals of recent European ancestries with genome interrogation grows still more rapidly and it is likely to be many years before sample sizes for genome interrogation in even major continental groups are close to proportional to relative population sizes. Thus, it is critical to optimize PRS performance for diverse populations in as many ways as we can. Given the substantial and growing fraction of the US population with genomes admixed from different continental ancestries, we believe that high quality PRS for much of the US population is unlikely to be achieved without properly accounting for local ancestries. Similarly, focused strategies to identify high-impact but population-specific variants could improve the quality of PRS in populations with such alleles. DNA variants from regions with a signature of natural selection often demonstrate such properties, and have been shown to be enriched among top associations for a number of hematological and immune/inflammatory traits that are important biomarkers for key chronic diseases. We propose to focus our PRS studies on hematological and immune/inflammatory traits and their associated chronic diseases and to extend methods for the development of PRS to accommodate estimates of local ancestry, high impact population-specific variants and multiple endophenotypes. Thus, our Specific Aims are: 1) Assemble and harmonize data sets needed to accomplish the goals of the project, including hematological traits (red blood cell, white blood cell, platelet), and immune/inflammatory traits (CRP, fibrinogen, D-dimer) from: Jackson Heart Study, Women’s Health Initiative, BioVU, and GeneSTAR. 2) Extend PRS methods to: a) explicitly model local ancestry; b) accommodate large-effect but population-specific risk alleles (such as those from regions with a signature of natural selection); and c) enable joint modeling of multiple endophenotypes; and 3) Develop and apply novel PRS and overall disease prediction models to: a) estimate risk of common diseases and related biomarkers affected by hematological, thrombotic and immune/inflammatory biology; and b) enable calculation of PRS-adjusted clinical laboratory values to reduce structural health disparities.

摘要 从全基因组关联研究（GWAS）中鉴定出的大量疾病易感性位点是 使多基因风险评分（PRS）能够兑现其改善健康结果和改变 个性化医疗的实践。常见病和相关疾病的PRS质量下降 近代非洲、亚洲和美洲原住民祖先群体相对于非洲、亚洲和美洲原住民祖先群体的数量性状 然而，最近欧洲血统的人口有可能造成一种新的不平等， 根据减贫战略提供保健服务。非欧洲血统的个体数量 审讯现在比五年前增长得快得多;然而， 最近的欧洲祖先与基因组审讯增长更快，这可能是许多年， 即使是在主要的大陆群体中，基因组调查的样本量也接近于 相对人口规模。因此，关键是要优化PRS性能的不同人群， 尽可能多的方式。鉴于美国人口中有相当大的一部分拥有基因组， 来自不同大陆血统的混合，我们认为，对于大多数美国人口来说， 如果不适当考虑当地的祖先，就不太可能实现。同样，重点战略， 识别高影响力但人群特异性的变异可以提高PRS在具有这种变异的人群中的质量。 等位基因来自具有自然选择特征的区域的DNA变体通常表现出这种特性， 已被证明是丰富的顶级协会之间的一些血液学和 免疫/炎症特征是关键慢性疾病的重要生物标志物。我们建议将重点放在 血液学和免疫/炎症特征及其相关慢性疾病的PRS研究， 扩展PRS的开发方法，以适应当地血统的估计，高影响 群体特异性变异和多种内表型。因此，我们的具体目标是：1）聚集和 协调完成项目目标所需的数据集，包括血液学特征（红色） 血细胞、白色血细胞、血小板）和免疫/炎症特征（CRP、纤维蛋白原、D-二聚体），来自：杰克逊 心脏研究，妇女健康倡议，BioVU和GeneSTAR。2)将PRS方法扩展到：a）显式 模型本地祖先; B）适应大效应但人群特异性风险等位基因（如那些 来自具有自然选择特征的区域）;以及c）使得能够对多个 内表型;和3）开发和应用新的PRS和整体疾病预测模型，以： 评估受血液学、血栓性和免疫学影响的常见疾病和相关生物标志物的风险， 免疫/炎症生物学;和B）能够计算PRS调整临床实验室值， 减少结构性健康差距。