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.

项目概要 该提案的目标是描述和量化 (a) 性别、(b) 与性别相关的暴露、 (c) 它们对整个医学现象中的遗传性疾病的相互作用。日益增长的可用性 具有与生物样本相关的电子健康记录 (EHR) 的大型生物银行创造了强大但 旨在了解性和性别相关影响的研究机会仍然相对未开发 暴露对人类健康的影响。美国国家人类基因组研究所（NHGRI）组织了 电子病历和基因组学 (eMERGE) 网络将各地的研究人员聚集在一起 美国促进基于电子病历的基因组研究和基因组医学的实施。我们有 在两个最初的 eMERGE 中心之间建立了新的合作关系，利用资源和 每个站点的现有基础设施包括总计超过 900 万条患者记录和超过 100,000 与 EHR 相关的基因分型样本。像范德比尔特和西北人口这样的大型患者群体 能够大规模研究性和性别相关暴露及其相互作用的关键资源 跨越临床现象。我们的初步数据表明，性和性别相关的暴露 包括社会经济地位和性侵犯创伤可以从医疗记录中挖掘出来。而且， 我们发现这些因素与大约 30% 的医学现象显着相关。最后，我们提供 有证据表明，性和与性别相关的接触也会降低复杂疾病的遗传风险。这些 研究结果得出了我们的中心假设，即性别和与性别相关的暴露相互作用，以改变 遗传性复杂疾病的风险。基于这些初步数据，我们的首要目标是识别和验证 性别和性别相关暴露对临床现象的影响。在目标 2 中，我们采用了遗传 流行病学方法来识别 1,051 名临床使用的遗传结构中的性别差异 实验室测试。最后，在目标 3 中，我们将这两方面的探究结合在一起，以测试临床是否 多基因风险评分（PRS）的表现会因性别和性别相关暴露而改变。这 拟议的研究包括旨在调查遗传、 导致大量复杂疾病发展的临床和心理社会危险因素 具有全表型数据和关联基因型的样本。这些性别意识分析可以被认为是 精准医学方法中必不可少但目前缺失的部分。