Genetic Studies of Blood Cell Traits in Multi-Ethnic Cohorts

 描述(由申请人提供)：血细胞特性，包括血红蛋白水平、红细胞(RBC)、白细胞(WBC)和血小板计数，是各种心血管、血液、肿瘤、免疫学和感染性疾病的重要中间临床表型。这些特征的分布在不同种族之间差别很大。例如，进一步深入了解非裔美国人(AA)中“民族性中性粒细胞减少症”的遗传决定因素，可能会对癌症患者在艾滋病毒感染风险、镰状细胞疾病严重程度或中性粒细胞或造血干细胞动员方面的健康差异产生影响。我们的初步数据同样表明，与非拉美裔白人相比，拉美裔美国人的血细胞特征分布存在重要差异。因此，拟议的研究可能会通过提供新的治疗途径而产生直接的临床影响，特别是对患有低血压病的少数族裔患者。 血细胞计数(个性化医学)，并阐明了与血细胞计数种族差异相关的遗传因素导致美国慢性炎症性疾病和血栓性疾病风险健康差异的新机制。尽管遗传因素在解释血细胞性状变异方面很重要，但在美国少数民族中，我们对特定基因座对这些性状的影响的了解仍然存在巨大的差距。巧合的是，遗传学界认为多种族GWAs在基因定位方面更有效。然而，在祖先不同的人群中，很少有血细胞特征的测序辅助GWA，而在拉美裔/拉丁裔(HLS)中则没有。因此，需要创新的方法来研究多种族队列中的血细胞特性，特别是那些最近混合的血细胞特性，如AA和HL，它们在以前的GWAs中一直被低估。第一次尝试绘制再生障碍性贫血的血细胞特征基因图谱时，没有将基于序列的非洲特定含量纳入推定，样本量有限，也没有考虑到当地血统，这主要是因为缺乏可用的方法和资源。重要的是，在HL中还没有进行过血细胞特性的GWA。对于拟议的研究，我们的团队现在已经收集了一个新的、更大的AA(n~34K)、HL(n~26K)和欧洲人(EU)(n~30K)的集合，并将利用我们在归因、本地血统推断和关联分析方面的最新方法学进展来增加我们对血细胞性状遗传学的知识。我们提出了以下目标。目的1.定位AA(n~34K)家系血细胞性状基因图谱。目的2.首次对占3向地方血统的HL(n~26K)的血细胞性状进行测序分析。目的3.跨多种族数据集的Meta分析，标注和验证新的关联信号。

 DESCRIPTION (provided by applicant): Blood cell traits, including hemoglobin level, red blood cell (RBC), white blood cell (WBC), and platelet counts, are important intermediate clinical phenotypes for a variety of cardiovascular, hematologic, oncologic, immunologic and infectious disease. The distributions of these traits differ considerably across ethnicities. For example, further insight into the genetic determinants of "ethnic neutropenia" in African Americans (AA) may have implications for health disparities in risk of HIV infection, sickle cell disease severity or mobilization of neutrophils or hematopoietic stem cells in cancer patients. Our preliminary data similarly suggest important differences in the distribution of blood cell traits in Hispanics compared to non-Hispanic whites. Therefore, the proposed studies are likely to have direct clinical impact by providing new avenues for treatment, particularly for minority patients with low blood counts (Personalized Medicine), and illuminating new mechanisms by which genetic factors related to ethnic differences in blood cell counts contribute to U.S. health disparities fo risk of chronic inflammatory and thrombotic diseases. Despite the importance of genetic factors in explaining variation in blood cell traits, there remains a huge gap in our knowledge of the contribution of specific loci to these traits among U.S. minorities. Coincidentally, multiethnic GWAS has been recognized as more powerful for gene mapping by the genetics community. However, there are very few sequencing-aided GWAS for blood cell traits in ancestrally diverse populations, and none in Hispanics/Latinos (HLs). Consequently, innovative methods are needed to study blood cell traits in multiethnic cohorts, particularly those recently admixed such as AA and HL, which have been under- represented in prior GWAS. The first attempts to map genes for blood cell traits in AA did not incorporate sequence based African specific content into the imputation, were limited in sample size, and did not accounted for local ancestry, mainly due to the lack of available methods and resources. Importantly, no GWAS have been conducted in HL for blood cell traits. For the proposed studies, our team has now assembled a new, larger collection of AA (n~34K), HL (n~26K) and Europeans (EU) (n~30K), and will leverage our recent methodological advances in imputation, local ancestry inference, and association analysis to increase our knowledge of blood cell trait genetics. We propose the following Aims. Aim 1. Map genes for blood cell traits in AA (n~34K) accounting for local ancestry. Aim 2. Conduct the first sequencing-aided GWAS of blood cell traits in HL (n~26K) accounting for 3- way local ancestry. Aim 3. Meta-analyze across multi-ethnic datasets, annotate and validate novel association signals.