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One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Veteranos , Humanos , Masculino , Variación Genética , Estudios Longitudinales , Polimorfismo de Nucleótido Simple , Estados Unidos , United States Department of Veterans Affairs , FemeninoRESUMEN
Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.
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Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10-9). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10-15). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0×10-4) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10-11) and glaucoma (OR=0.82, P=6.9×10-9). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.
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Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.
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Distrofia Endotelial de Fuchs , Humanos , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/metabolismo , Estudio de Asociación del Genoma Completo , Factor de Transcripción 4/genética , Colágeno , Laminina/genéticaRESUMEN
Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.
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Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto , Humanos , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/genética , Población Negra/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. Methods : We developed and validated EHR-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in three independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet one of three criteria: 1) two or more dates with any DR ICD-9/10 code documented in the EHR, or 2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or 3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology exam. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology exam. Results: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.97 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV=0.94; NPV=0.86) and lower in MGB (PPV=0.84; NPV=0.76). In comparison, use of DR definition as implemented in Phenome-wide association study (PheWAS) in VUMC, yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62,000 DR cases with genetic data including 14,549 African Americans and 6,209 Hispanics with DR. Conclusions/Discussion: We demonstrate the robustness of the algorithms at three separate health-care centers, with a minimum PPV of 0.84 and substantially improved NPV than existing high-throughput methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.
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PURPOSE: The study's primary aims were to describe the long-term speech outcomes for adolescents and young adults with a history of childhood apraxia of speech (CAS) and to examine the association of persistent speech sound errors with measures of literacy skills, phonological processing, motor speech production, and parent report of early motor difficulty. METHOD: Data from a large longitudinal 25-year study were used to explore outcomes for 32 individuals with a history of CAS, ages 12;6 (years;months) to 25 years (M = 17.4, SD = 4.7). Persistent and nonpersistent groups were compared on decoding, phonological processing, multisyllabic word repetition, diadochokinetic rate, and parent report of motor involvement. Parametric (Welch's t tests) and nonparametric tests (Wilcoxon and Fisher exact tests) were used to identify differences between the groups' distributions. Developmental trajectories of speech production were plotted. RESULTS: Outcomes for individuals with CAS are highly variable, with some demonstrating speech sound errors into adolescence and young adulthood. Speech sound errors were primarily on later developing sounds. Persistence was significantly associated with early motor difficulties. Difficulties with multisyllabic words, phonological processing, and literacy were often present regardless of persistence or nonpersistence of speech errors. CONCLUSIONS: Children with CAS are at risk for persistent speech sound errors into adulthood. For children showing limited progress with more traditional speech therapy, alternative interventions should be explored. Individuals with persistent speech sound errors are more likely to have a history of early motor deficits. Regardless of persistence, participants with CAS demonstrated ongoing weaknesses in literacy, phonological processing skills, and complex speech production tasks.
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Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.
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Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular pathophysiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program (MVP) and meta-analyzed with the previous largest FECD GWAS, finding twelve significant loci (eight novel). We further confirmed the TCF4 locus in admixed African and Hispanic/Latino ancestries, and found an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and co-localization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.
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PURPOSE: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.
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Diabetes Mellitus , Distrofia Endotelial de Fuchs , Femenino , Humanos , Distrofia Endotelial de Fuchs/epidemiología , Distrofia Endotelial de Fuchs/genética , Distrofia Endotelial de Fuchs/diagnóstico , Multimorbilidad , Córnea , Factores de Riesgo , Endotelio Corneal , Diabetes Mellitus/epidemiologíaRESUMEN
Diabetes onset precedes diabetic retinopathy (DR) by 5-10 years, but many people with diabetes remain free of this microvascular complication. Our aim was to identify risk factors for DR progression in a unique and diverse population, the slums of Mumbai. We performed a nested case-control study of 1163 diabetics over 40 years of age from slums in 18 wards of Mumbai. Data was collected on 33 variables and assessed for association with DR using both univariate and multivariate analyses. Stratified analyses were also performed on males and females, separately. Among hypertensive individuals we also assessed whether duration of hypertension associated with DR. Of 31 non-correlated variables analysed as risk factors for DR, 15 showed evidence of significant association. The most prominent included sex, where being a female associated with decreased odds of DR, while longer duration of diabetes and poor glycaemic control associated with increased odds. The duration of diabetes effect was partially, but significantly, mediated by age of diabetes diagnoses (8.6% of variance explained, p = 0.012). Obesity as measured by several measures, including body mass index (BMI) and measures of central obesity had a negative association with DR; increased measures of obesity consistently reduced odds of DR. As in most earlier studies, DR was associated with the duration of diabetes and glycaemic control. However, other factors, especially obesity related measures were associated with DR, in ways that contrast with most prior studies. These results indicated that the overall pattern of association in the Mumbai slums was novel. Thus, in previously uncharacterized populations, such as the slums that we examined, it is important to evaluate all risk factors de novo to appropriately assess patterns of association as the patterns of association with DR can be complex and population specific.
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A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.
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Glaucoma de Ángulo Abierto , Veteranos , Humanos , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/diagnóstico , Biología Computacional , Factores de Riesgo , Hispánicos o Latinos/genética , Polimorfismo de Nucleótido SimpleRESUMEN
[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].
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SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk. CONCLUSION: Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.
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Longevidad , Insuficiencia Renal Crónica , Humanos , Estudios de Cohortes , Estudios Prospectivos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/complicaciones , Genómica , Progresión de la Enfermedad , Factores de RiesgoRESUMEN
Pathogenic variants on the X-chromosome can have more severe consequences for hemizygous males, while heterozygote females can avoid severe consequences due to diploidy and the capacity for nonrandom expression. Thus, when an allele is more common in females this could indicate that it increases the probability of early death in the male hemizygous state, which can be considered a measure of pathogenicity. Importantly, large-scale genomic data now makes it possible to compare allele proportions between the sexes. To discover pathogenic variants on the X-chromosome, we analyzed exome data from 125,748 ancestrally diverse participants in the Genome Aggregation Database (gnomAD). After filtering out duplicates and extremely rare variants, 44,606 of the original 348,221 remained for analysis. We divided the proportion of variant alleles in females by the proportion in males for all variant sites, and then placed each variant into one of three a priori categories: (1) Reference (Primarily synonymous and intronic), (2) Unlikely-to-be-tolerated (Primarily missense), and (3) Least-likely-to-be-tolerated (Primarily frameshift). To assess the impact of ploidy, we compared the distribution of these ratios between pseudoautosomal and non-pseudoautosomal regions. In the non-pseudoautosomal regions, mean female-to-male ratios were lowest among Reference (2.40), greater for Unlikely-to-be-tolerated (2.77) and highest for Least-likely-to-be-tolerated (3.28) variants. Corresponding ratios were lower in the pseudoautosomal regions (1.52, 1.57, and 1.68, respectively), with the most extreme ratio being just below 11. Because pathogenic effects in the pseudoautosomal regions should not drive ratio increases, this maximum ratio provides an upper bound for baseline noise. In the non-pseudoautosomal regions, 319 variants had a ratio over 11. In sum, we identified a measure with a dataset specific threshold for identifying pathogenicity in non-pseudoautosomal X-chromosome variants: the female-to-male allele proportion ratio.
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Exoma , Heterocigoto , Cromosoma X , Femenino , Humanos , Masculino , Cromosomas , Virulencia , Cromosoma X/genéticaRESUMEN
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.
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Purpose: The purpose of the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study is to identify non-genetic and genetic risk factors associated with diabetic retinopathy (DR). This report examines the non-genetic risk factors for DR in South Indian patients.Methods: Participants with South Indian ancestry and type 2 diabetes (T2D) were included from two sources: the Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. Fundus photography and optical coherence tomography (OCT) were obtained on participants. Fundus images were graded for DR severity and OCTs were graded for center-involved diabetic macular edema (ciDME). Multivariate analyses were performed using stepwise logistic regression to assess effects of the demographic and clinical factors on proliferative DR (PDR) and DME.Results: Among the 2941 participants with DR grading, participants with PDR were more likely to be younger [odds ratio (OR)=0.95], men (OR = 1.83), have a longer duration of diabetes (OR = 1.10), have a higher hemoglobin A1c (OR = 1.12), have albuminuria (OR = 5.83), have hypertension (OR = 1.69), have a higher HDL (OR = 1.02) and a lower total cholesterol (OR = 0.99) (all p < 0.05). Among the 483 participants with gradable OCT scans, participants who had ciDME were more likely to be younger (OR = 0.97), men (OR = 2.80), have a longer duration of diabetes (OR = 1.06), have lower triglycerides (OR = 0.99), and have albuminuria (OR = 3.12) (all p < 0.05).Conclusions: Younger age, male sex, longer duration of diabetes, higher HbA1c, and presence of albuminuria were identified as risk factors for PDR and DME in a South Indian population with T2D.
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Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Edema Macular , Albuminuria/complicaciones , Albuminuria/diagnóstico , Albuminuria/genética , Colesterol , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Retinopatía Diabética/complicaciones , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/genética , Hemoglobina Glucada , Humanos , Edema Macular/etiología , Edema Macular/genética , Masculino , Estudios Prospectivos , Factores de Riesgo , TriglicéridosRESUMEN
PURPOSE: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS). DESIGN: Cross-sectional study. PARTICIPANTS: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls. METHODS: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS. MAIN OUTCOME MEASURES: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS. RESULTS: GRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases. CONCLUSIONS: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.