Elucidating the phenome-wide impact of sex and gender on disease

阐明性和性别对疾病的全表组影响

• 批准号: 10308237
• 负责人: Lea K Davis
• 金额: $ 61.82万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308237
• 关键词: Academic Medical Centers; Age of Onset; Awareness; Biological; Biological Markers; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Clinical; Complex; Computerized Medical Record; Data; Development; Diagnosis; Disclosure; Disease; Disease Outcome; Electronic Health Record; Electronic Medical Records and Genomics Network; Female; Gender; Genes; Genetic; Genetic Diseases; Genetic Risk; Genomic medicine; Genomics; Genotype; Genotype-Tissue Expression Project; Goals; Gynecologic; Health; Heritability; Human; Incidence; Infrastructure; Knowledge; Laboratories; Lead; Letters; Link; Lipids; Longevity; Major Depressive Disorder; Medical; Medical Records; Medicine; Mental disorders; National Human Genome Research Institute; Obesity; Outcome; Pain; Patients; Pharmaceutical Preparations; Polycystic Ovary Syndrome; Population; Poverty; Prevalence; Procedures; Records; Regulation; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Sensitivity and Specificity; Severities; Sex Bias; Sex Differences; Sex Differentiation; Site; Socioeconomic Status; Substance abuse problem; Symptoms; Testing; Testosterone; Training; Trauma; White Blood Cell Count procedure; Work; base; biobank; cardiovascular disorder risk; clinically actionable; clinically relevant; cohort; comorbidity; diagnostic biomarker; disorder risk; genetic architecture; genetic epidemiology; genome wide association study; genome-wide; genotypic sex; human disease; male; personalized approach; phenome; polygenic risk score; precision medicine; psychosocial; sex; sexual assault; success; trait

PROJECT SUMMARY The goal of this proposal is to characterize and quantify the impact of (a) sex, (b) gender-related exposures, and (c) their interactions on heritable disease across the entire medical phenome. The growing availability of large-scale biobanks with electronic health records (EHRs) linked to biospecimens has created a powerful, but still relatively untapped, opportunity for research aimed at understanding the impact of sex and gender-related exposures on human health. The National Human Genome Research Institute (NHGRI) organized the Electronic Medical Records and Genomics (eMERGE) network which brought together investigators around the U.S. to facilitate EHR-based genomic research and the implementation of genomic medicine. We have created a new collaborative between two of the original eMERGE centers that leverages the resources and existing infrastructure at each site including a combined total of over 9 million patient records and over 100,000 genotyped samples linked to EHRs. Large patient cohorts like the Vanderbilt and Northwestern populations are critical resources that enable research on sex and gender-related exposures and their interaction at scale across the clinical phenome. Our preliminary data demonstrates that sex and gender-related exposures including socioeconomic position and sexual assualt trauma can be mined from the medical record. Moreover, we show that these factors are significantly associated with ~30% of the medical phenome. Finally, we provide evidence that sex and gender-related exposures also moderate genetic risk for complex disease. These findings lead to our central hypothesis that sex and gender-associated exposures interact to modify risk for heritable complex diseases. Building on this preliminary data, our first Aim is to identify and validate the effects of sex and gender-related exposures across the clinical phenome. In Aim 2 we employ a genetic epidemiology approach to identify sex-differences in the genetic architecture of 1,051 clinically utilized laboratory tests. Finally, in Aim 3 we bring these two lines of inquiry together to test whether the clinical manifestations of polygenic risk scores (PRS) are modified by sex and gender-related exposures. The proposed research includes both quantitative and qualitative analyses aimed at investigating the genetic, clinical, and psychosocial risk factors that contribute to the development of complex disease in extremely large samples with phenome-wide data and linked genotypes. These sex-aware analyses can be thought of as essential, but currently missing, pieces of the precision approach to medicine.

项目摘要 该建议的目的是表征和量化（a）性别的影响，（b）与性别相关的暴露， （c）他们在整个医学现象中就可遗传疾病的相互作用。日益增长的可用性 具有电子健康记录（EHRS）的大型生物银行与生物群有关 仍然相对尚未开发的研究机会，旨在了解性别和性别相关的影响 暴露于人类健康。国家人类基因组研究所（NHGRI）组织了 电子病历和基因组学（Emerge）网络，将调查人员汇集在一起 美国促进基于EHR的基因组研究和基因组医学的实施。我们有 在两个原始出现的中心之间创建了一个新的合作，以利用资源和 每个站点的现有基础设施，包括总计超过900万例患者记录和超过100,000 与EHR相关的基因分型样品。范德比尔特和西北人口等大型患者队列 能够研究性和性别相关的暴露及其大规模互动的关键资源 在整个临床现象中。我们的初步数据表明性别和与性别相关的暴露 可以从病历中开采包括社会经济地位和性侵害创伤。而且， 我们表明，这些因素与〜30％的医学现象显着相关。最后，我们提供 性别和与性别相关的暴露也适度对复杂疾病的遗传风险进行了证据。这些 发现导致我们的核心假设，即性别和性别相关的暴露相互作用以修改 遗传复杂疾病的风险。在此初步数据的基础上，我们的第一个目的是识别和验证 性别和性别相关的暴露在整个临床现象中的影响。在AIM 2中，我们采用遗传 流行病学方法是鉴定1,051种临床利用的遗传结构中的性别差异 实验室测试。最后，在AIM 3中，我们将这两条询问带在一起，以测试是否临床 多基因风险评分（PR）的表现通过性别和与性别相关的暴露来改变。这 拟议的研究包括旨在研究遗传的定量和定性分析。 临床和社会心理危险因素，导致非常大的复杂疾病发展 带有全面数据和链接基因型的样品。这些性意识分析可以被认为是 必不可少但目前缺少的医学精确方法。