Multi-ethnic high-throughput study to identify novel non-HLA genetic contributors to mortality after blood and marrow transplantation

Project Summary Blood and marrow transplant (BMT) is an effective cure for many life-threatening hematologic diseases. Survival after BMT has improved dramatically over the past two decades, however up to 40% of patients still die within one year after HLA-matched unrelated donor allogeneic BMT. This project will build upon our prior genome-wide (GWAS) and exome-wide association studies (ExWAS) involving ~2,900 patients named Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT (DISCOVeRY-BMT). Our GWAS identified several donor loci that significantly increased recipient’s risk of disease-related mortality (DRM) and donor-recipient genotype mismatches significantly increased risk of transplant-related mortality (TRM) in European Americans (EAs). Our ExWAS discovered a rare nonsynonymous coding variant, where a donor-recipient genotype mismatch correlated with TRM and additional novel genes (e.g. TEX38, OR51D1, and NT5E) correlated with overall survival, TRM and DRM. Our goal for this proposal is two-fold: to deepen our understanding of non-HLA genetic contributors to BMT mortality, and to build the clinical-genomic prognostic models to translate such understanding into clinical practice. The first goal will be fulfilled in two directions. 1) We will systematically survey both rare and common variants using whole-exome sequencing (WES) and meta- GWAS in EAs as well as under-studied diverse populations in an effort to bridge the BMT survival disparity between EAs, African Americans, Asians and Hispanics. Our prior ExWAS in EAs demonstrated the important roles played by rare coding variants in BMT mortality, however, only 2% of rare variants are in the exome array. Therefore, we will use WES to assay all exonic variants in 5,598 multi-ethnic donor-recipient pairs. As the variants/genes we identify are direct candidates for causality, functional validation will be performed to investigate such relationships. In parallel, we will perform the largest meta-GWAS of BMT mortality to date. Through our collaborations, we have assembled all BMT GWAS data available in the US (8,576 donor-recipient pairs including 1,978 minority pairs). 2) We will interrogate WES and GWAS data to further reveal the biological networks contributing to BMT mortality. To meet the second goal, we will leverage our unique and powerful GWAS resource to develop prognostic models to predict patients’ personalized mortality risk. This is the first study to use next-generation sequencing technology to analyze the contribution of non-HLA coding variants on post-BMT mortality. GWAS data on 8,576 donor-recipient pairs, of which 5,598 pairs also have WES data, will make this the largest genetic study ever undertaken, and provide a real opportunity to understand the genetics of BMT mortality across diverse populations. The prognostic models we develop will provide a valuable tool to help reduce BMT mortality and enhance donor-recipient matching in routine clinical practice. Importantly, the data generated by this project will be shared publicly to serve as a resource for additional research to improve survivorship after BMT and enhance the public investment in this project.