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

项目摘要 本提案的目标是描述和量化以下因素的影响：（a）性别，（B）与性别有关的暴露， 以及（c）它们在整个医学表型中对遗传性疾病的相互作用。越来越多的可用性 大规模的生物银行与电子健康记录（EHR）连接到生物标本，创造了一个强大的，但 仍然相对未开发的研究机会，旨在了解性和与性别有关的 对人体健康的影响。国家人类基因组研究所（NHGRI）组织了 电子医疗记录和基因组学（eMERGE）网络，该网络将研究人员聚集在一起， 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 在两个最初的eMERGE中心之间建立了一个新的合作关系， 每个站点的现有基础设施，包括总计超过900万份患者记录和超过10万份 与EHR相关的基因型样本。像范德比尔特和西北大学这样的大型患者群体 关键资源，使研究性和性别相关的风险及其相互作用的规模 在临床表现上。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。此外，委员会认为， 我们发现这些因素与约30%的医学现象显著相关。最后，我们提供 有证据表明，性和与性别有关的暴露也会降低复杂疾病的遗传风险。这些 研究结果导致了我们的中心假设，即性和性别相关的暴露相互作用， 遗传性复杂疾病的风险。在这些初步数据的基础上，我们的第一个目标是识别和验证 性别和性别相关暴露对整个临床表型的影响。在目标2中， 一种流行病学方法来确定1,051例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，我们将这两条调查路线结合在一起，以测试临床是否 多基因风险评分（PRS）的表现是由性别和性别相关的暴露修改。的 拟议的研究包括定量和定性分析，旨在调查遗传， 临床和心理社会风险因素，有助于复杂疾病的发展， 具有全表型数据和连锁基因型的样本。这些性别意识分析可以被认为是 关键的，但目前缺少的，精确的医学方法的片段。

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.