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

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.