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JAMA Ophthalmol. 2019 Aug 22. doi: 10.1001/jamaophthalmol.2019.3109. [Epub ahead of print]

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

Author information

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

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.

PMID:
31436842
PMCID:
PMC6707005
[Available on 2020-08-22]
DOI:
10.1001/jamaophthalmol.2019.3109

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