[Skip to Content]
[Skip to Content Landing]
Views 839
Citations 0
Brief Report
August 22, 2019

Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis

Author Affiliations
  • 1Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear, Boston
  • 2Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 3Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 4Channing Division of Network Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts
  • 5Marshfield Clinic Research Institute, Marshfield, Wisconsin
  • 6Department of Ophthalmology, University of North Carolina, Chapel Hill
  • 7Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City
  • 8Department of Anatomy/Cell Biology, University of Iowa, College of Medicine, Iowa City
  • 9Scripps Genome Center, University of California at San Diego, San Diego
  • 10The Emmes Corporation, Rockville, Maryland
  • 11Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina
  • 12Department of Medicine, Duke University Medical Center, Durham, North Carolina
  • 13Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts
  • 14Department of Biostatistics, Harvard T. H. Chan School of Public Health, Harvard Medical School, Boston, Massachusetts
  • 15Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
  • 16Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
  • 17Department of Cellular Biology and Anatomy, Augusta University, Augusta, Georgia
  • 18Wills Eye Hospital, Philadelphia, Pennsylvania
  • 19Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
  • 20Department of Ophthalmology, WVU Eye Institute, Morgantown, West Virginia,
  • 21Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, Ohio
  • 22Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York
  • 23Department of Ophthalmology, NYU Langone Medical Center, NYU School of Medicine, New York, New York
  • 24Department of Ophthalmology, Stanford University, Palo Alto, California
  • 25Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
  • 26Department of Genetics, Stanford University, Palo Alto, California
  • 27Department of Ophthalmology, Hamilton Glaucoma Center and Shiley Eye Institute, University of California at San Diego, La Jolla
  • 28Wilmer Eye Institute, Johns Hopkins University Hospital, Baltimore, Maryland
  • 29Department of Ophthalmology, Icahn School of Medicine, Mount Sinai Hospital, New York
JAMA Ophthalmol. 2019;137(10):1190-1194. doi:10.1001/jamaophthalmol.2019.3109
Key Points

Question  Is a genetic risk score (GRS) using 12 primary open-angle glaucoma genetic risk variants associated with the age at diagnosis?

Findings  In this cross-sectional study of 3108 individuals with primary open-angle glaucoma, each higher GRS unit was associated with an earlier age at diagnosis, and affected individuals in the top 5% of the GRS had an earlier age at diagnosis compared with those in the bottom 5% GRS.

Meaning  These findings suggest aggregate primary open-angle glaucoma genetic risk variants can influence clinically relevant disease features such as age at diagnosis.

Abstract

Importance  Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations.

Objective  To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis.

Design, Setting, and Participants  A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018.

Main Outcomes and Measures  Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression.

Results  The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10−66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = −0.36; 95% CI, −0.56 to −0.16; P = 4.0 × 10−4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10−4).

Conclusions and Relevance  A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

×