InterLymph Consortium: interrogating pleiotropy and gene by environment interactions among hematopoietic malignancies.

摘要 大多数淋巴瘤和多发性骨髓瘤（MM）是由无限制的克隆性生长因子引起的恶性肿瘤。 B细胞在不同成熟阶段的增殖。近二十年来，国际淋巴瘤组织 流行病学（InterLymph）联盟系统地揭示了遗传性和非遗传性淋巴瘤 MM的危险因素我们的目标是建立在近20年的成功合作， 该联盟将开展迄今为止最大的淋巴瘤和MM全基因组关联研究（GWAS）， 评估淋巴瘤多基因风险评分的性能，并确定基因-环境 与疾病易感性相关的相互作用。这将解决关键问题：具体而言，我们能否充分 阐明与MM、HL和NHL亚型易感性相关的遗传变异？基因是如何 侧写有重叠吗这些特征如何与环境风险因素相互作用？更精确地说， 是否可以将各种因素结合起来，以帮助进行风险预测？在目标1中，我们将进行最大的全基因组 迄今为止，在约60，000例淋巴瘤病例中进行了相关性研究（GWAS），包括HL（N=约6，700）、NHL （N=~ 36，000）和MM（N=~ 16，000）以及超过197，000例对照。在目标2中，我们将开发多基因风险 评分（PRS），包括在13，700例淋巴瘤的独立系列中进行PRS验证 患者在目标3中，我们将在选择上下文中评估GWAS和亚型特异性PRS。 环境暴露数据，以获得对疾病关系的新见解， 发现仅在特定环境触发物存在下起作用的新易感基因座。最后在 目标4，我们将为InterLymph联盟创建一个平台中心。这个平台叫做数据 协调中心（DCC），将确保该领域最相关，最前沿的假设驱动 研究问题可以在InterLymph Consortium的资源范围内应用。通过这个项目， 我们的目标是激活InterLymph研究人员的集体智慧和资源，以扩大 我们对遗传变异和环境如何影响淋巴瘤风险的理解， 这可能有助于临床实践。

ABSTRACT Most lymphomas and multiple myeloma (MM) are malignancies resulting from the unrestrained clonal proliferation of B-cells at different stages of maturation. For nearly two decades, the International Lymphoma Epidemiology (InterLymph) Consortium has systematically uncovered genetic and non-genetic lymphoma and MM risk factors. We aim to build upon nearly 20 years of successful collaboration within the InterLymph Consortium to undertake the largest genome-wide association study (GWAS) of lymphomas and MM to date, to assess the performance of polygenic risk scores for lymphomas, and to identify gene-environment interactions associated with disease susceptibility. This will address key questions: specifically, can we fully elucidate the genetic variants involved in susceptibility MM, HL, and NHL subtypes? How do the genetic profiles overlap? How do these profiles interact with the environmental risk factors? With further precision, can factors be combined to assist in risk prediction? In Aim 1, we will undertake the largest genome wide association study (GWAS) to date of ~60,000 lymphoma cases, including HL (N=~6,700), NHL (N=~36,000) and MM (N=~16,000) and over 197,000 controls. In Aim 2, we will develop polygenic risk scores (PRS), including conducting a validation of the PRS in an independent series of 13,700 lymphoma patients. In Aim 3, we will evaluate GWAS and subtype-specific PRS in the context of select environmental exposure data to gain novel insight into exposure-disease relationships and potentially uncover novel susceptibility loci which act only in the presence of specific environmental triggers. Finally, in Aim 4, we will create a platform hub for the InterLymph Consortium. This platform, called the Data Coordinating Center (DCC), will ensure that the field's most pertinent, cutting edge hypothesis driven research questions can be applied within the resources of the InterLymph Consortium. Through this project, we aim to activate the collective intelligence and resources of the InterLymph researchers in order to expand our understanding of how genetic variants and the environment influence risk of lymphomas and explore how this may assist clinical practice.