Exploring the shared genetic architecture of white blood cell variation and childhood acute lymphoblastic leukemia

项目总结/摘要 急性淋巴细胞白血病（ALL）是一种白色血细胞的癌症，是最常见的恶性肿瘤 在15岁以下的儿童中。尽管治疗取得了重大进展，但ALL幸存的儿童仍面临着 严重的长期治疗相关疾病。此外，ALL仍然是癌症相关疾病的主要原因之一。 儿童死亡率。因此，预防儿童ALL仍然是一个重要目标， 了解这种疾病的病因，这是本研究的重点。 全基因组关联研究（GWAS）已经确定了儿童ALL的遗传风险因素， 几个基因，其中许多控制白色血细胞（WBC）的发展，包括IKZF 1，ARID 5 B， CEBPE。与ALL风险相关的大多数变异也与WBC性状的变异相关， 这表明正常血细胞发育和血癌之间有共同的遗传基础。因此 对遗传性白细胞性状变异在儿童ALL风险中的作用进行全面研究是必要的。本 最后，本研究的第一个目的是对与WBC性状变异相关的常见遗传变异进行编目， 即通过GWAS计数淋巴细胞、单核细胞、中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞和总WBC 使用来自约330，000名欧洲血统的无癌症个体的遗传和血细胞表型数据 和免疫相关疾病，来自英国生物库研究。 第二个目标是评估WBC性状相关变异对儿童风险的贡献。 ALL通过：（1）使用来自欧洲的GWAS结果测试这些变异与儿童ALL的关联- 一项来自加州癌症记录连锁项目的祖先病例对照研究，包括1184例ALL病例 和3551名对照，在一个独立的GWAS中复制了959例ALL病例的新风险位点。 儿童肿瘤组和来自Wellcome Trust病例对照联盟的2624例对照;以及（2） 在孟德尔随机化分析中使用WBC性状相关变异作为遗传工具， 每种WBC特征与儿童ALL风险的因果关系。 我们的最终目的是确定与儿童ALL相关的假定致病基因，并评估其对儿童ALL的影响。 通过全转录组关联研究， （TWAS）使用全血基因表达的遗传预测模型。我们将在以下方面执行TWAS：（1） ALL病例对照研究，以发现与ALL风险相关的基因表达;（2）英国 生物库数据，以确定基因的表达也与每个WBC性状。这将是第一 检查WBC指数和ALL风险之间的因果关系。我们的研究结果将揭示 ALL的生物学，提供了对ALL风险基因通过WBC相关的 这可能会突出风险分层和预防的潜在途径。

PROJECT SUMMARY/ABSTRACT Acute lymphoblastic leukemia (ALL) is a cancer of white blood cells, and the most common malignancy in children under 15 years of age. Despite significant advances in treatment, children who survive ALL face severe long-term therapy-related morbidities. Moreover, ALL is still one of the leading causes of cancer-related mortality in children. Prevention of childhood ALL, therefore, remains an essential goal, and is dependent on understanding the etiology of this disease, which forms the focus of this study. Genome-wide association studies (GWAS) have identified genetic risk factors for childhood ALL at several genes, many of which control white blood cell (WBC) development, including IKZF1, ARID5B, and CEBPE. The majority of variants associated with ALL risk are also associated with variation in WBC traits, suggesting a shared genetic basis between normal blood cell development and blood cancer. Thus, a comprehensive study of the role of heritable WBC trait variation in risk of childhood ALL is warranted. To this end, the first aim of this study is to catalog common genetic variants associated with variation in WBC traits, namely counts of lymphocytes, monocytes, neutrophils, eosinophils, basophils, and total WBCs, via GWAS using genetic and blood cell phenotype data from ~330,000 individuals of European ancestry, free of cancer and immune-related disease, from the UK Biobank study. The second aim will be to assess the contribution of WBC trait-associated variants to risk of childhood ALL by: (1) testing association of these variants with childhood ALL using GWAS results from a European- ancestry case-control study from the California Cancer Records Linkage Project, including 1184 ALL cases and 3551 controls, with replication of novel risk loci in an independent GWAS of 959 ALL cases from the Children's Oncology Group and 2624 controls from the Wellcome Trust Case Control Consortium; and (2) using the WBC trait-associated variants as genetic instruments in Mendelian randomization analyses to test the causal relevance of each WBC trait in risk of childhood ALL. Our final aim is to identify putative causal genes associated with childhood ALL, and to assess the shared biological pathways underlying WBC trait variation, through transcriptome-wide association studies (TWAS) using genetic prediction models of whole blood gene expression. We will perform TWAS in: (1) the ALL case-control study, to discover genes the expression of which is associated with ALL risk; and (2) the UK Biobank data to identify genes whose expression is also associated with each WBC trait. This will be the first examination of the causal relationship between WBC indices and ALL risk. Our results will shed light on the biology of ALL, provide insight into the extent to which ALL risk genes operate via WBC-associated mechanisms, and may highlight potential avenues for risk-stratification and prevention.