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

项目总结 这项建议的目标是描述和量化(A)性接触的影响，(B)与性别有关的暴露， 以及(C)他们在整个医学现象中对遗传性疾病的相互作用。日益增长的可用性 具有电子健康记录(EHR)的大规模生物库与生物群落相关联，创造了一个强大的、但 仍然相对未被开发，旨在理解性和与性别相关的影响的研究机会 对人类健康的暴露。国家人类基因组研究所(NHGRI)组织了 电子病历和基因组学(Emerge)网络将研究人员聚集在一起 美国为基于EHR的基因组研究和基因组医学的实施提供便利。我们有 在两个原始Emerge中心之间创建了新的协作，利用资源和 每个站点的现有基础设施包括总计900多万份患者记录和100,000多份 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患者队列是 能够研究性接触和与性别有关的暴露及其相互作用的关键资源 在临床表型上。我们的初步数据表明，性和与性别相关的暴露 包括社会经济地位和性创伤可以从医疗记录中挖掘出来。此外， 我们表明，这些因素与约30%的医学现象显著相关。最后，我们提供 有证据表明，性接触和与性别相关的暴露也会降低复杂疾病的遗传风险。这些 这些发现导致了我们的中心假设，即性和与性别相关的暴露相互作用，以改变 可遗传的复杂疾病的风险。在此初步数据的基础上，我们的首要目标是确定和验证 性接触和与性别相关的暴露对整个临床表型的影响。在《目标2》中，我们使用了一种基因 用流行病学方法鉴定1,051例临床使用的遗传结构的性别差异 实验室检测。最后，在目标3中，我们将这两条线结合在一起来测试临床 多基因风险评分(PR)的表现因性别和与性别有关的暴露而改变。这个 拟议的研究包括定量和定性分析，旨在调查遗传， 临床和心理社会危险因素在极大程度上促进了复杂疾病的发展 具有表型范围数据和连锁基因类型的样本。这些性别意识的分析可以被认为是 精准的医学方法是必不可少的，但目前尚不具备。

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.