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

Bao Jian Fan; Jessica Cooke Bailey; Rob P. Igo; Jae H. Kang; Tahani Boumenna; Murray H. Brilliant; Donald L. Budenz; John H. Fingert; Terry Gaasterland; Douglas Gaasterland; Michael A. Hauser; Peter Kraft; Richard K. Lee; Paul R. Lichter; Yutao Liu; Syoko E. Moroi; Jonathan S. Myers; Margaret A. Pericak-Vance; Anthony Realini; Douglas J. Rhee; Julia E. Richards; Robert Ritch; Joel S. Schuman; William K. Scott; Kuldev Singh; Arthur J. Sit; Douglas Vollrath; Robert N. Weinreb; Gadi Wollstein; Donald J. Zack; Jonathan L. Haines; Louis R. Pasquale; Janey L. Wiggs

doi:10.1001/jamaophthalmol.2019.3109

Brief Report

August 22, 2019

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

Bao Jian Fan, MD, PhD¹; Jessica Cooke Bailey, PhD, MA^2,3; Rob P. Igo Jr, PhD³; et al Jae H. Kang, ScD⁴; Tahani Boumenna, BA¹; Murray H. Brilliant, PhD⁵; Donald L. Budenz, MD, MPH⁶; John H. Fingert, MD, PhD^7,8; Terry Gaasterland, PhD⁹; Douglas Gaasterland, MD¹⁰; Michael A. Hauser, PhD^11,12; Peter Kraft, PhD^13,14; Richard K. Lee, MD, PhD¹⁵; Paul R. Lichter, MD¹⁶; Yutao Liu, MD, PhD¹⁷; Syoko E. Moroi, MD¹⁶; Jonathan S. Myers, MD¹⁸; Margaret A. Pericak-Vance, PhD¹⁹; Anthony Realini, MD²⁰; Douglas J. Rhee, MD²¹; Julia E. Richards, PhD¹⁶; Robert Ritch, MD²²; Joel S. Schuman, MD²³; William K. Scott, PhD¹⁹; Kuldev Singh, MD²⁴; Arthur J. Sit, SM, MD²⁵; Douglas Vollrath, MD, PhD²⁶; Robert N. Weinreb, MD²⁷; Gadi Wollstein, MD²³; Donald J. Zack, MD, PhD²⁸; Jonathan L. Haines, PhD^2,3; Louis R. Pasquale, MD²⁹; Janey L. Wiggs, MD, PhD¹

Author Affiliations Article Information

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

Original Investigation

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

The Genetics of Glaucoma in People of African Descent (GGLAD) Consortium; Michael A. Hauser, PhD; R. Rand Allingham, MD; Tin Aung, MD, PhD; Carly J. Van Der Heide, MD; Kent D. Taylor, PhD; Jerome I. Rotter, MD; Shih-Hsiu J. Wang, MD, PhD; Pieter W. M. Bonnemaijer, MD; Susan E. Williams, MD; Sadiq M. Abdullahi, MD; Khaled K. Abu-Amero, PhD; Michael G. Anderson, PhD; Stephen Akafo, MD; Mahmoud B. Alhassan, MD; Ifeoma Asimadu, MD; Radha Ayyagari, PhD; Saydou Bakayoko, MD; Prisca Biangoup Nyamsi, MD; Donald W. Bowden, PhD; William C. Bromley, MD; Donald L. Budenz, MD; Trevor R. Carmichael, MD, PhD; Pratap Challa, MD; Yii-Der Ida Chen, PhD; Chimdi M. Chuka-Okosa, MD; Jessica N. Cooke Bailey, PhD; Vital Paulino Costa, MD; Dianne A. Cruz, MS; Harvey DuBiner, MD; John F. Ervin, BA; Robert M. Feldman, MD; Miles Flamme-Wiese, BSE; Douglas E. Gaasterland, MD; Sarah J. Garnai, BS; Christopher A. Girkin, MD; Nouhoum Guirou, MD; Xiuqing Guo, PhD; Jonathan L. Haines, PhD; Christopher J. Hammond, MD; Leon Herndon, MD; Thomas J. Hoffmann, PhD; Christine M. Hulette, MD; Abba Hydara, MD; Robert P. Igo Jr, PhD; Eric Jorgenson, PhD; Joyce Kabwe, MD; Ngoy Janvier Kilangalanga, MD; Nkiru Kizor-Akaraiwe, MD; Rachel W. Kuchtey, MD, PhD; Hasnaa Lamari, MD; Zheng Li, MD, PhD; Jeffrey M. Liebmann, MD; Yutao Liu, PhD; Ruth J.F. Loos, PhD; Monica B. Melo, PhD; Sayoko E. Moroi, MD, PhD; Joseph M. Msosa, MD; Robert F. Mullins, PhD; Girish Nadkarni, MD; Abdoulaye Napo, MD; Maggie C. Y. Ng, PhD; Hugo Freire Nunes, PhD; Ebenezer Obeng-Nyarkoh, MA; Anthony Okeke, MD; Suhanya Okeke, MD; Olusegun Olaniyi, MD; Olusola Olawoye, MD; Mariana Borges Oliveira, MD; Louise R. Pasquale, MD; Rodolfo A. Perez-Grossmann, MD; Margaret A. Pericak-Vance, PhD; Xue Qin, PhD; Michele Ramsay, PhD; Serge Resnikoff, MD, PhD; Julia E. Richards, PhD; Rui Barroso Schimiti, MD; Kar Seng Sim, MS; William E. Sponsel, MD; Paulo Vinicius Svidnicki, PhD; Alberta A. H. J. Thiadens, MD, PhD; Nkechinyere J. Uche, MD; Cornelia M. van Duijn, PhD; José Paulo Cabral de Vasconcellos, MD, PhD; Janey L Wiggs, MD, PhD; Linda M. Zangwill, PhD; Neil Risch, PhD; Dan Milea, MD, PhD; Adeyinka Ashaye, MD; Caroline C. W. Klaver, MD, PhD; Robert N. Weinreb, MD; Allison E. Ashley Koch, PhD; John H. Fingert, MD, PhD; Chiea Chuen Khor, MD, PhD

Full Text

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.

Full Text

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

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