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) 是由不受限制的克隆引起的恶性肿瘤 B细胞在不同成熟阶段的增殖。近二十年来，国际淋巴瘤 流行病学（InterLymph）联盟系统地发现了遗传性和非遗传性淋巴瘤 和 MM 风险因素。我们的目标是在 InterLymph 内部近 20 年的成功合作基础上再接再厉 联盟将开展迄今为止最大规模的淋巴瘤和多发性骨髓瘤全基因组关联研究 (GWAS)， 评估淋巴瘤多基因风险评分的表现，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：具体来说，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？遗传是怎样产生的 个人资料重叠？这些概况如何与环境风险因素相互作用？随着精度的进一步提高， 能否结合因素来辅助风险预测？在目标 1 中，我们将进行最大的基因组范围 迄今为止约 60,000 例淋巴瘤病例的关联研究 (GWAS)，包括 HL (N=约 6,700)、NHL (N=~36,000) 和 MM (N=~16,000) 以及超过 197,000 个对照。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，我们将在选择的背景下评估 GWAS 和特定于亚型的 PRS 环境暴露数据，以获得对暴露与疾病关系的新见解，并可能 发现仅在存在特定环境触发因素时起作用的新的易感性位点。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，称为数据 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 联盟的资源范围内应用。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并探索如何 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.