Paul Auer

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer's disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole genome sequencing of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European American (EA) ancestry group compared to those of Hispanic American (HA), African American (AA), and East Asian (EAS) ancestry. Further, we identified two genes (CFHR1 and LRP6) that harbor multiple rare, putatively deleterious variants associated with mLOY susceptibility, show that subsets of human hematopoietic stem cells are enriched for activity of mLOY susceptibility variants, and that certain alleles on chromosome Y are more likely to be lost than others.

To the Editor: Myelodysplastic syndromes (MDS) refer to a heterogeneous class of diseases that affect the ability of hematopoietic stem cells to mature into healthy blood cells. The prognosis for MDS is variable but wellestablished risk scoring systems can effectively delineate the risks of death and progression to acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative therapy for MDS and approximately 30% of MDS patients eventually undergo allo-HCT. 1 The National Marrow Donor Program (NMDP)/Be The Match maintains a large stem cell donor registry that can be searched for potential matches for allo-HCT. For each patient that requires an allo-HCT, a related donor match is attempted. In patients for which a related donor is not available, the NMDP registry is searched for unrelated donors based on a variety of characteristics including HLA-type …

Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods focus only on participants with distinct primary continental ancestry without accommodating recently-admixed individuals with mosaic continental ancestry backgrounds for different segments of their genomes. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals. GAUDI explicitly models ancestry-differential effects while borrowing information across segments with shared ancestry in admixed genomes. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses for traits with associated variants exhibiting ancestral-differential effects. Leveraging data from the Women’s Health Initiative study, we show that GAUDI improves PRS prediction of white blood cell count and C-reactive protein in African …

Relapse represents the major cause of allogeneic hematopoietic cell transplantation (allo-HCT) failure in patients with MDS. Recurrent somatic mutations have been shown to be prognostic of relapse. However, there remains considerable uncertainty in determining relapse risk for an individual patient. To discover novel determinants of relapse after allo-HCT, we conducted comprehensive genome-wide association analyses using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).MethodsWhole genome sequencing (WGS) data on 494 patients with MDS who received allo-HCT from 2014 to 2018 were analyzed. Somatic variants were called by OCTOPUS pipeline. Germline single nucleotide variants (SNVs) were called by GATK pipelines. Structural variants (SVs) were called by Parliament2 and Chromoseq pipelines. Associations with post-transplant relapse (REL) by …

Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P< 5× 10− 9) at 7 new loci for FVIII (ST3GAL4 …

Multiple myeloma (MM) is the second most common hematologic malignancy in the US [1]. MM is preceded by an asymptomatic premalignant condition termed monoclonal gammopathy of undetermined significance (MGUS), with an annual rate of progression from MGUS to MM of about 1%[2]. While the majority of MGUS patients do not progress to overt MM, some patients could have progression rates as high as 58% in 20 years [3]. Despite differences in the risk of malignant transformation, current guidelines for MGUS recommend “watchful waiting” until the disease progresses to symptomatic MM, often manifesting as overt end-organ damage before treatment can begin. While no current treatment can prevent MGUS progressing into overt MM, identifying those patients who have a higher risk of progression could lessen the burden of the disease and extend long-term remission by early intervention. The large …

Background: We previously characterized point mutations of clonal hematopoiesis (CH) including single nucleotide variants or small insertion/deletions residing in a set of cancer-related genes (e.g., DNMT3A and TET2), and found that CH point mutations occurred at a much higher prevalence in childhood cancer survivors (CCS) than in age-sex-race matched community controls. However, mosaic chromosomal alterations (mCAs), another form of CH with megabase-scale structural alterations (copy gain, copy loss and copy-neutral loss of heterozygosity), have not been examined. Methods: Detection of mCAs was performed on whole-genome sequencing (WGS, 30X) data from 5-year CCS with the Mosaic Chromosomal Alterations (MoChA) caller which utilizes phased genotypes, coverage, and B allele frequency (BAF) at heterozygous sites (HETS). We implemented the pipeline established by the TOPMed …

Disease relapse remains a major barrier to success after allogeneic hematopoietic cell transplantation (allo-HCT) in myelodysplastic neoplasms (MDS). While certain high risk genomic alterations are associated with increased risk of relapse, there is a lack of clinically applicable tools to analyze the downstream cellular events that are associated with relapse. We hypothesized that unique proteomic signatures in MDS patients undergoing allo-HCT could serve as a tool to understand this aspect and predict relapse. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 52 MDS patients who underwent allo-HCT and analyzed their proteomic profile from pretransplant blood samples in a matched case-control design. Twenty-six patients without disease relapse after allo-HCT (controls) were matched with 26 patients who experienced relapse (cases). Proteomics …