non-European Individuals Research Articles

The intersection of big data and healthcare innovation: millennial perspectives on precision medicine technology

Precision medicine (PM) is an approach to healthcare that customizes treatment and prevention strategies based on individual characteristics such as genetics, environment, and lifestyle. By utilizing detailed data from diverse populations, precision medicine aims to provide accurate and effective medical care tailored to each person’s unique profile. This approach relies on the diversity of local populations which is increasingly captured through large-scale data sets, often referred to as Big Data. Due to the underrepresentation of non-European individuals in human genetic studies, many countries with diverse and underrepresented populations must build their own reference database due to a lack of holistic global perspective. This research investigated a population sub-group to better understand the factors shaping their attitudes of PM adoption in an Asian developed context. This research was based on the millennial generation in Singapore (born between 1981 and 1996). The study employed a quantitative online survey, based on the TAM theoretical framework. A total of 377 valid responses were received and the results were analysed using the structural equation modelling (SEM) technique. Results showed that perceived data security, subjective technical knowledge, trust in government, subjective norm and perceived usefulness influenced the attitude of millennials towards precision medicine and provided relevant insights for the successful implementation of PM approach in the future.

Rare forms of monogenic diabetes in non-European individuals. First reports of CEL and RFX6 mutations from the Indian subcontinent.

Monogenic diabetes is one of the few examples in metabolic diseases in which a real precision medicine approach can be implemented in daily clinical work. Unfortunately, most of what is known today comes from studies in Whites, thus leaving much uncertainty about the genetics and the clinical presentation of monogenic diabetes in non-Europeans. To fill this gap, we report here two pedigrees from Bangladesh with CEL- and RFX6- diabetes, two rare types of monogenic diabetes which have never been described so far in individuals of the Indian subcontinent. Next generation, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) were performed. Variants' interpretation was according to the American College of Medical Genetics and Genomics guidelines. In the pedigree with CEL-diabetes, a large and never described deletion of exon 2-11 of CEL (confirmed by MLPA) affecting the entire catalytic domain and being likely pathogenic (LP) was observed in both the proband (who had diabetes at 16) and his mother (diabetes at 31), but not in relatives with normoglycemia. In the pedigree with RFX6-diabetes, a LP protein truncation variant (PTV, p.Tyr192*) in RFX6 was found in both the proband (diabetes at 9) and his mother (diabetes at 30), thus suggesting high heterogeneity in disease onset. Normoglycemic relatives were not available for genetic testing. We report genetic features and clinical presentation of the first two cases of CEL- and RFX6-diabetes from the Indian subcontinent, thus contributing to fill the gap of knowledge on monogenic diabetes in non-Europeans.

PAPRIKA: A Question Bank for Assessing Psoriatic Arthritis Risk in Individuals of Diverse Ancestries.

We aimed to create a question bank about clinical factors for predicting the diagnoses of psoriatic arthritis in patients with psoriasis of various ancestries and skin tones, which can be completed entirely by patients. Utah Psoriasis Initiative participants without a psoriatic arthritis diagnosis at enrollment were observed for diagnosis during the study period. We inferred ancestry from exome sequencing data and performed Cox proportional hazards regression to identify clinical predictors of psoriatic arthritis in different ancestry groups. Based on results and literature review, we developed a question bank for assessing psoriatic arthritis risk among patients with psoriasis in various ancestries. Patient-reported untreated psoriasis induration and history of fingernail psoriasis were associated with psoriatic arthritis in participants of European and non-European ancestry. We developed the Psoriatic Arthritis Prediction and Identification Question Bank for Diverse Ancestries (PAPRIKA) version 1.0, which included questions regarding psoriasis characteristics, arthritis symptoms, comorbidities, family history, and demographics. PAPRIKA is accessible at http://bjfenglab.org/. The clinical features (untreated psoriasis induration and history of fingernail psoriasis) that can predict psoriatic arthritis in European individuals also work for non-European individuals. PAPRIKA can be used to gather psoriatic arthritis predictive data from patients with psoriasis without provider assistance and is relevant for patients across ancestries.

Plasma proteomic associations with genetics and health in the UK Biobank

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand–receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public–private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.

Association of Polygenic Risk Scores for Hearing Difficulty in Older Adults With Hearing Loss in Mid-Childhood and Midlife

Although more than 200 genes have been associated with monogenic congenital hearing loss, the polygenic contribution to hearing decline across the life course remains largely unknown. To examine the association of polygenic risk scores (PRSs) for self-reported hearing difficulty among adults (40-69 years) with measured hearing and speech reception abilities in mid-childhood and early midlife. This was a population-based cross-sectional study nested within the Longitudinal Study of Australian Children that included 1608 children and 1642 adults. Pure tone audiometry, speech reception threshold against noise, and genetic data were evaluated. Linear and logistic regressions of PRSs were conducted for hearing outcomes. Study analysis was performed from March 1 to 31, 2022. Genotypes were generated from saliva or blood using global single-nucleotide polymorphisms array and PRSs derived from published genome-wide association studies of self-reported hearing difficulty (PRS1) and hearing aid use (PRS2). Hearing outcomes were continuous using the high Fletcher index (mean hearing threshold, 1, 2, and 4 kHz) and speech reception threshold (SRT); and dichotomized for bilateral hearing loss of more than 15 dB HL and abnormal SRT. Included in the study were 1608 children (mean [SD] age, 11.5 [0.5] years; 812 [50.5%] male children; 1365 [84.9%] European and 243[15.1%] non-European) and 1642 adults (mean [SD] age, 43.7 [5.1] years; 1442 [87.8%] female adults; 1430 [87.1%] European and 212 [12.9%] non-European individuals). In adults, both PRS1 and PRS2 were associated with hearing thresholds. For each SD increment in PRS1 and PRS2, hearing thresholds were 0.4 (95% CI, 0-0.8) decibel hearing level (dB HL) and 0.9 (95% CI, 0.5-1.2) dB HL higher on the high Fletcher index, respectively. Each SD increment in PRS increased the odds of adult hearing loss of more than 15 dB HL by 10% to 30% (OR for PRS1, 1.1; 95% CI, 1.0-1.3; OR for PRS2, 1.3; 95% CI, 1.1-1.5). Similar but attenuated patterns were noted in children (OR for PRS1, 1.1; 95% CI, 0.8-1.2; OR for PRS2, 1.2; 95% CI, 1.0-1.5). Both PRSs showed minimal evidence of associations with speech reception thresholds or abnormal SRT in children or adults. This population-based cross-sectional study of PRSs for self-reported hearing difficulty among adults found an association with hearing ability in mid-childhood. This adds to the evidence that age-related hearing loss begins as early as the first decade of life and that polygenic inheritance may play a role together with other environmental risk factors.

Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort.

We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483.

Enrichment analyses identify shared associations for 25 quantitative traits in over 600,000 individuals from seven diverse ancestries

SummarySince 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals because of various confounding challenges. Here, we demonstrate that enrichment analyses that aggregate SNP-level association statistics at multiple genomic scales—from genes to genomic regions and pathways—have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. We identify 1,000 gene-level associations that are genome-wide significant in at least two ancestry cohorts across these 25 traits as well as highly conserved pathway associations with triglyceride levels in European, East Asian, and Native Hawaiian cohorts.

Significant sparse polygenic risk scores across 813 traits in UK Biobank.

We present a systematic assessment of polygenic risk score (PRS) prediction across more than 1,500 traits using genetic and phenotype data in the UK Biobank. We report 813 sparse PRS models with significant (p < 2.5 x 10-5) incremental predictive performance when compared against the covariate-only model that considers age, sex, types of genotyping arrays, and the principal component loadings of genotypes. We report a significant correlation between the number of genetic variants selected in the sparse PRS model and the incremental predictive performance (Spearman's ⍴ = 0.61, p = 2.2 x 10-59 for quantitative traits, ⍴ = 0.21, p = 9.6 x 10-4 for binary traits). The sparse PRS model trained on European individuals showed limited transferability when evaluated on non-European individuals in the UK Biobank. We provide the PRS model weights on the Global Biobank Engine (https://biobankengine.stanford.edu/prs).

A functional genomics approach in Tanzanian population identifies distinct genetic regulators of cytokine production compared to European population

Humans exhibit remarkable interindividual and interpopulation immune response variability upon microbial challenges. Cytokines play a vital role in regulating inflammation and immune responses, but dysregulation of cytokine responses has been implicated in different disease states. Host genetic factors were previously shown to significantly impact cytokine response heterogeneity mainly in European-based studies, but it is unclear whether these findings are transferable to non-European individuals. Here, we aimed to identify genetic variants modulating cytokine responses in healthy adults of East African ancestry from Tanzania. We leveraged both cytokine and genetic data and performed genome-wide cytokine quantitative trait loci (cQTLs) mapping. The results were compared with another cohort of healthy adults of Western European ancestry via direct overlap and functional enrichment analyses. We also performed meta-analyses to identify cQTLs with congruent effect direction in both populations. In the Tanzanians, cQTL mapping identified 80 independent suggestive loci and one genome-wide significant locus (TBC1D22A) at chromosome 22; SNP rs12169244 was associated with IL-1b release after Salmonella enteritidis stimulation. Remarkably, the identified cQTLs varied significantly when compared to the European cohort, and there was a very limited percentage of overlap (1.6% to 1.9%). We further observed ancestry-specific pathways regulating induced cytokine responses, and there was significant enrichment of the interferon pathway specifically in the Tanzanians. Furthermore, contrary to the Europeans, genetic variants in the TLR10-TLR1-TLR6 locus showed no effect on cytokine response. Our data reveal both ancestry-specific effects of genetic variants and pathways on cytokine response heterogeneity, hence arguing for the importance of initiatives to include diverse populations into genomics research.

Multi-ancestry eQTL meta-analysis of human brain identifies candidate causal variants for brain-related traits.

While large-scale, genome-wide association studies (GWAS) have identified hundreds of loci associated with brain-related traits, identification of the variants, genes and molecular mechanisms underlying these traits remains challenging. Integration of GWAS with expression quantitative trait loci (eQTLs) and identification of shared genetic architecture have been widely adopted to nominate genes and candidate causal variants. However, this approach is limited by sample size, statistical power and linkage disequilibrium. We developed the multivariate multiple QTL approach and performed a large-scale, multi-ancestry eQTL meta-analysis to increase power and fine-mapping resolution. Analysis of 3,983 RNA-sequenced samples from 2,119 donors, including 474 non-European individuals, yielded an effective sample size of 3,154. Joint statistical fine-mapping of eQTL and GWAS identified 329 variant-trait pairs for 24 brain-related traits driven by 204 unique candidate causal variants for 189 unique genes. This integrative analysis identifies candidate causal variants and elucidates potential regulatory mechanisms for genes underlying schizophrenia, bipolar disorder and Alzheimer's disease.

Abstract 9855: Bayesian Multivariate Genetic Analysis of Lipids Improves Translational Insight

Introduction: Genome-wide association studies (GWAS) of blood lipids have yielded several translational insights for coronary artery disease. Hypothesis: We tested the hypothesis that novel Bayesian methods leveraging genetic correlation can improve insights from lipid genetics analyses. Methods: We used published lipids GWAS results from 297,626 participants of the Million Veterans Program (MVP), and generated summary statistics for 276,096 participants of the UK Biobank. We employed a multivariate adaptive shrinkage (mashR) model to each dataset. MashR allows the effect of a SNP to be modeled as a mixture of multivariate normal distributions across lipid levels (LDL-C, HDL-C, Total Cholesterol, and triglycerides) and an empirical Bayes approach to appropriately nudge the posterior estimates of the effect in accordance with the overall patterns observed in the data. Results: In addition to reproducing all 318 loci significantly associated with lipids in MVP, we identified 4,689 novel loci associated with lipids using mashR. We observed a high degree of agreement between MVP and UK Biobank, with over 95% of UKBB replicated in MVP and an additional 1246 identified. In genetic prioritization analyses, mashR shows improvement in the detection of known Mendelian genes and the consistency of ranks among subgroups compared with univariate results. Our approach improves the estimate of enrichment parameters of known genomic features similar to established GWAS variants. Finally, combining these joint estimates with tools for incorporating the genetic correlation structure, mashR improves the proportion of variation explained by lipid polygenic risk scores by up to 58% (se 0.015) when compared to univariate substrates across lipid traits. This improvement holds across both European and non-European individuals. We show that much of this gain in power arises from improved precision of the posterior estimates where the ratio of original standard error over posterior marginal variance reflects an increased ‘effective sample size’. Conclusions: Our framework shows that Bayesian multivariate genetic analysis markedly improves power for genomic discovery, better identifies causal genes, and improves polygenic risk prediction for complex traits.

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals.

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N=463), average European ancestry was significantly higher than noncarriers (N=708; p=.011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR=0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.

240-OR: Combining Type 2 Diabetes Polygenic Scores Improves Prediction in 36,000 European and Non-European Participants in the Partners Healthcare Biobank

Polygenic scores constructed by the aggregation of effect sizes of associated genetic variants have been shown to predict type 2 diabetes (T2D). Polygenic scores can be defined as “restricted-to-significant polygenic scores” (rsPS), and “globally expanded polygenic scores” (gePS), which can include millions of variants beyond those that are genome-wide significant. Most polygenic scores have been generated based on genome-wide association studies (GWAS) conducted predominantly in participants of European ancestry (EU); how these polygenic scores perform in non-European individuals in the healthcare system has not been thoroughly evaluated. We applied the rsPS and gePS for T2D in 30,240 EU participants, 3,029 Latinos (LA), and 2,201 African Americans (AA) from the Partners HealthCare Biobank, which maintains blood and DNA samples from patients seen at Partners HealthCare-affiliated hospitals in Boston. We compared rsPS based on the DIAMANTE consortium meta-analysis, with 398 variants (rsPS_398), rsPS based on the latest Million Veterans Program meta-analysis, with 682 variants (rsPS_682), and a gePS based on ldpred, including 6.9M variants adjusted for their effects based on linkage disequilibrium. rsPS_682 was most strongly associated with T2D in all ancestries (OR per SD in EU=1.73 p=7×10-142, OR per SD in LA =1.88, p=7×10-19, OR per SD in AA =1.47, p=1×10-8 compared to the other polygenic scores. We observed that rsPS_682 and the gePS provided both complementary information, and that combining them into the model improved the prediction in all ancestries, with 16%, 22%, and 16% increase in accuracy in EU, LA, and AA, respectively. We show the advantage of combining rsPS and gePS to improve prediction of T2D in multi-ethnic populations within a healthcare system. The results suggest that larger and multi-ethnic T2D GWAS are needed to avoid major health disparities. Disclosure J.M. Mercader: None. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. A. Leong: None. V. Kaur: None. M. Udler: None. J.B. Meigs: Consultant; Self; Quest Diagnostics. B. Porneala: None. Funding American Diabetes Association (1-19-ICTS-068 to J.M.M.)

Genotyping Array Design and Data Quality Control in the Million Veteran Program

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Using the Data We Have: Improving Diversity in Genomic Research

The shortage of genomic research data in persons of non-European ancestry is impeding our ability to use genomics in the clinical care of non-European individuals. Improved efforts to utilize data on non-European populations will increase the quality of genomic research and the inferences drawn from it for people of all backgrounds.

Psychopharmacology and ethnicity: A comparative study on Senegalese and Italian men

Objectives: Ethnicity represents a crucial factor in influencing response to psychotropic drugs. Some data indicate that functional polymorphisms of two candidate genes of the serotonin (5-HT) transporter (SERT) may affect the response to selective 5-HT reuptake inhibitors (SSRIs). The present study aimed to compare the platelet SERT, through the specific [3H]paroxetine ([3H]Par) binding, and plasma oxytocin (OT) levels in 20 Senegalese and in 20 Italian men.Methods: No subjects had family or personal history of any major psychiatric disorder, or had ever regularly taken psychotropic drugs, or were suffering from any physical illness.Results: Senegalese men showed statistically significant higher density (Bmax, fmol/mg protein, mean ± SD) of [3H]Par binding sites (2105.00 ± 473.15 vs 1139.85 ± 213.58, P < 0.001), as well as more elevated plasma OT levels (pg/ml, mean ± SD) (OT: 18.08 ± 4.46 vs 6.62 ± 2.91) than Italian men.Conclusions: These differences, possibly due to genetic or dietary reasons, or even to gender, might affect the response to psychopharmacological compounds. Our findings would suggest specific caution when administering psychotropic compounds to non-European individuals, and the need of further studies in this emerging field of neuropsychopharmacology.

The Resources of Others

Abstract The Resources of Others. Dutch Exploitation of European Expansion and Empires, 1570-1800 Historiography pertaining to the study of European colonial empires can generally be defined in two different strands: on the one hand, the nationally geared scholarship that zooms in on the development of specific ‘national’ empires and their relationships to non-European individuals, groups and polities and, on the other hand, narratives that privilege the focus on the colony and the colony’s links to the outside world. What neither of these strands does, however, is to question the role foreigners played in the capturing of resources within the logic of a foreign empire and how those resources were transferred to the places of origin of these individuals and groups. This article provides an overview of Dutch participation in the empires of others (English, French, Spanish and Portuguese) by underlining the important role that Dutch merchants, investors and labour specialists played in the exploitation of other, often competing, European empires. While some of the acquired resources remained in the host society where Dutch merchants and firms settled, some of the colonial resources and by-products were sent back to the merchants’ and firms’ places of origin, more often than not through complex transnational networks of contacts and divergent groups of interests.

EPIGEN-Brazil Initiative resources: a Latin American imputation panel and the Scientific Workflow.

EPIGEN-Brazil is one of the largest Latin American initiatives at the interface of human genomics, public health, and computational biology. Here, we present two resources to address two challenges to the global dissemination of precision medicine and the development of the bioinformatics know-how to support it. To address the underrepresentation of non-European individuals in human genome diversity studies, we present the EPIGEN-5M+1KGP imputation panel—the fusion of the public 1000 Genomes Project (1KGP) Phase 3 imputation panel with haplotypes derived from the EPIGEN-5M data set (a product of the genotyping of 4.3 million SNPs in 265 admixed individuals from the EPIGEN-Brazil Initiative). When we imputed a target SNPs data set (6487 admixed individuals genotyped for 2.2 million SNPs from the EPIGEN-Brazil project) with the EPIGEN-5M+1KGP panel, we gained 140,452 more SNPs in total than when using the 1KGP Phase 3 panel alone and 788,873 additional high confidence SNPs (info score ≥ 0.8). Thus, the major effect of the inclusion of the EPIGEN-5M data set in this new imputation panel is not only to gain more SNPs but also to improve the quality of imputation. To address the lack of transparency and reproducibility of bioinformatics protocols, we present a conceptual Scientific Workflow in the form of a website that models the scientific process (by including publications, flowcharts, masterscripts, documents, and bioinformatics protocols), making it accessible and interactive. Its applicability is shown in the context of the development of our EPIGEN-5M+1KGP imputation panel. The Scientific Workflow also serves as a repository of bioinformatics resources.

A Late Pleistocene woman from Tham Lod, Thailand: the influence of today on a face from the past

Abstract

Combined Donor and Recipient Non-HLA Genotypes Show Evidence of Genome Wide Association with Transplant Related Mortality (TRM) after HLA-Matched Unrelated Donor Blood and Marrow Transplantation (URD-BMT) (DISCOVeRY-BMT study)

Transplant-related mortality (TRM) is the largest limiting factor to successful URD-BMT as curative therapy. Identification of non-HLA genetic factors in either recipients or donors could improve BMT outcomes through better matching at these loci. We performed a genome-wide association study (GWAS), named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) of 1-year TRM in 3,532 patients treated for AML, ALL or MDS (recipients) reported to CIBMTR from 2000-2011 and their HLA-matched URD (donors); donor DNA was available for 98% of HCT recipients. Cohort 1 includes 2,240 donor-recipient pairs; patients received a 10/10 HLA URD-BMT from 2000-08. Cohort 2 includes 823 donor-recipient pairs; patients received either a 10/10 HLA URD-BMT from 2009-11 or 8/8 (but <10/10) HLA URD-BMT. Genotyping of recipient and donor DNA was performed using the Illumina HumanOmniExpress-24 BeadChip containing 729,293 single nucleotide polymorphisms (SNPs) at University of Southern California. Due to the small number of non-European individuals, we report analyses of European American recipients only. After quality control, Cohort 1 includes 2,052 donor-recipient pairs and Cohort 2 includes 763 donor-recipient pairs typed at 637,655 SNPs. For each SNP, a shared genotype variable was created to capture donor-recipient allele sharing. The shared genotype was assigned a value of 0 if the recipient and donor have the same genotype at a given SNP and a value of 1 if they differ by 1 or 2 alleles. This idea, that a "matched" genotype can impact risk of TRM, is similar to the idea behind HLA matching. For all survival analyses we accommodated the competing risk of death due to disease; covariates including age, body mass index, and graft type (blood or marrow) were included in all analyses. Analyses of the shared genotype variable with TRM were run for all diseases together and excluding ALL (AML+MDS). P-values for each cohort were combined using METAL software with weights proportional to the square root of the number of cases. We report on results for combined P-value (Pmeta) <5 x 10-8.In analyses of AML+MDS donor-recipient pairs four typed SNPs, rs9884653, rs16850885, rs1246576 and rs10014791, spanning 865,040 base pairs in and near MTHFD2L and EPGN on chromosome 4q13.3 were significant at Pmeta <5 x 10-8; several SNPs in this region approach genome wide significance level. The most significant SNP, rs16850885 (P =7.6 x 10-7 in Cohort 1, P =6 x10-3 in Cohort 2, Pmeta =1.8 x 10-8) at 74,304,423 bp, places recipients who differ from their donors by at least one allele (5.2% of patients in Cohort 1 and 3.9% in Cohort 2) at a 2.6 fold increased risk of TRM (Tables 1 and 2). It is in perfect linkage disequilibrium (r2=1) with rs9884653 at 74,280,426 and rs10014791 at 75,145,466; rs1246576 is in strong linkage disequilibrium with rs16850885 (r2 =.91). All four SNPs shows hazard ratios (HRs) of similar magnitude across both cohorts for patients who differ from their donors by at least 1 allele. These SNPs are not associated with death due to disease in either cohort. The difference was not allele specific; of those patients who died of TRM with at least one allele difference approximately 50% of the donors provided the less common A allele (donor A/G or A/A with recipient G/G) and 50% of the recipients had the A allele (recipient A/G with a G/G donor). Analyses of the donors and recipients separately each show some evidence of association with the minor allele A at rs16850885 (Table 2), but it is patients who differ from their donors at this locus who have greatest risk of TRM.A previous GWAS showed that individuals with at least one copy of the A allele at rs16850885 have lower levels of secreted IL-1β following small pox vaccination compared with those who are homozygous GG (P =7.3 x 10-9). IL-1β, a pro-inflammatory cytokine secreted early in the inflammatory response, may be contributing to the risk of TRM through the combination of initiation and maintenance of host tissue inßammation and donor cell inßammatory response. Our study, DISCOVeRY-BMT, is the largest GWAS of TRM HLA-matched URD-BMT. Further confirmation of these findings in a third cohort may aid in donor selection. [Display omitted] [Display omitted] DisclosuresSucheston-Campbell:NIH/NHLBI: Research Funding. McCarthy:The Binding Site: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn:NIH/NHLBI: Research Funding; Novartis: Equity Ownership.