Glaucoma Genetic Risk Score in the Amish

Abstract

Purpose : Through the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study, we previously reported the prevalence and risk factors of glaucoma and established a significant presence of glaucoma in Amish communities in Holmes County, Ohio. The Amish have a homogeneous lifestyle with similar years of formal education, reducing the effect of confounding environmental factors for genetic studies. Over 120 risk loci have been identified for glaucoma in genome-wide association studies. The purpose of this study was to construct a Genetic Risk Score (GRS) for glaucoma and to determine whether the GRS was associated with glaucoma and whether the GRS showed the discriminatory ability for glaucoma in the Amish in Holmes County, Ohio.

Methods : We included 558 participants with genotype data, 61 clinically evaluated glaucoma statuses from the GGLEAM study and 497 self-reported prior glaucoma diagnoses based on the questionnaires from the Collaborative Amish Aging and Memory Project and the Amish Eye Study. After aligning alleles for risk, a GRS was constructed using the European ancestry-specific weighted sum of risk alleles of the published glaucoma-associated variants. A family-based association test between glaucoma and the GRS was performed using the ASSOC program in S.A.G.E. package adjusting for age at exam and sex. To evaluate the discriminatory ability of the GRS for glaucoma, we conducted receiver operating characteristic (ROC) analyses.

Results : There were 80 cases and 478 controls (61% female) and the mean of age at exam was 73.12 years (±12.18). Out of 127 published glaucoma-associated variants, 53 variants (11 matched and 42 proxies with R²>0.8) were available to construct GRS. The GRS ranged from -2.28 to 0.41 (mean -0.75±0.43) and was higher in cases than in controls (-0.62±0.46 vs. -0.78±0.42, p=0.002). The GRS was associated with glaucoma (p=0.01) after adjusting for age at exam and sex. ROC analysis of GRS yielded an area under the curve (AUC) of 0.61 (CI: 0.54-0.68).

Conclusions : In summary, we observed that the GRS comprising 53 previously reported glaucoma variants was associated with glaucoma in the Amish population. We also found that, even when using the subset of all known genetic susceptibility variants, the ancestry-matched GRS alone had a moderate discriminatory ability of glaucoma in the Amish in Holmes County, Ohio.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.