Glaucoma Genetic Risk Scores in the Million Veteran Program.

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.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

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.

Development and Evaluation of a Rules-based Algorithm for Primary Open-Angle Glaucoma in the VA Million Veteran Program.

The availability of electronic health record (EHR)-linked biobank data for research presents opportunities to better understand complex ocular diseases. Developing accurate computable phenotypes for ocular diseases for which gold standard diagnosis includes imaging remains inaccessible in most biobank-linked EHRs. The objective of this study was to develop and validate a computable phenotype to identify primary open-angle glaucoma (POAG) through accessing the Department of Veterans Affairs (VA) Computerized Patient Record System (CPRS) and Million Veteran Program (MVP) biobank. Accessing CPRS clinical ophthalmology data from VA Medical Center Eye Clinic (VAMCEC) patients, we developed and iteratively refined POAG case and control algorithms based on clinical, prescription, and structured diagnosis data (ICD-CM codes). Refinement was performed via detailed chart review, initially at a single VAMCEC (n = 200) and validated at two additional VAMCECs (n = 100 each). Positive and negative predictive values (PPV, NPV) were computed as the proportion of CPRS patients correctly classified with POAG or without POAG, respectively, by the algorithms, validated by ophthalmologists and optometrists with access to gold-standard clinical diagnosis data. The final algorithms performed better than previously reported approaches in assuring the accuracy and reproducibility of POAG classification (PPV >83% and NPV >97%) with consistent performance in Black or African American and in White Veterans. Applied to the MVP to identify cases and controls, genetic analysis of a known POAG-associated locus further validated the algorithms. We conclude that ours is a viable approach to use combined EHR-genetic data to study patients with complex diseases that require imaging confirmation.