Performance of Polygenic Risk Scores for Primary Open-Angle Glaucoma in Populations of African Descent.

Importance: Primary open-angle glaucoma (POAG) polygenic risk scores (PRSs) continue to be evaluated in primarily European-ancestry populations despite higher prevalence and worse outcomes in African-ancestry populations.

Objective: To evaluate how established POAG PRSs perform in African-ancestry samples from the Genetics in Glaucoma Patients of African Descent (GIGA), Genetics of Glaucoma in Individuals of African Descent (GGLAD), and Million Veteran Program (MVP) datasets and compare these with European-ancestry samples.

Design, Setting, And Participants: This was a multicenter, cross-sectional study of POAG cases and controls from Tanzania, South Africa, Nigeria, Ghana, and the US.

Risk Factors for Bacterial Keratitis and Severe Disease in Hydrogel Contact Lens Users: A Multicenter Case-Control Study and Case-Only Analysis.

Purpose: To assess risk factors for contact lens (CL)-related bacterial keratitis, cases and high-risk controls were enrolled. Using high-risk controls can help elucidate whether certain CL types or modalities are attributable to disease burden if risky wear patterns are similar between the cases and controls. This analysis identified whether such CL factors were associated with the occurrence of bacterial keratitis.

Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma.

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.

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

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.

A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

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.

Characterizing the pathogenicity of genetic variants: the consequences of context.

Beyond initial discovery of a pathogenic variant, establishing that a variant is recurrently associated with disease is important for understanding clinical impact and disease etiology. Disappointingly, our ability to characterize pathogenicity under varied circumstances is limited. Here we discuss the role of genetic and environmental background and how it affects variant penetrance and outcomes.

Development of Portable Electronic Health Record Based Algorithms to Identify Individuals with Diabetic Retinopathy.

Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. : 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.

Long-Term Outcomes for Individuals With Childhood Apraxia of Speech.

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 ( = 17.4, = 4.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

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.

Multi-ancestry GWAS of Fuchs corneal dystrophy highlights roles of laminins, collagen, and endothelial cell regulation.

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.

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.

Patterns of risk for diabetic retinopathy in the Mumbai slums: The Aditya Jyot Diabetic Retinopathy in Urban Mumbai Slums Study (AJ-DRUMSS) Report 3.

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.

Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program.

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.

Genomic Disorders in CKD across the Lifespan.

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.

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.

A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility.

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.

Hemizygosity can reveal variant pathogenicity on the X-chromosome.

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.

Younger Age and Albuminuria are Associated with Proliferative Diabetic Retinopathy and Diabetic Macular Edema in the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study.

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. 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.