Deep Ocular Phenotyping Across Primary Open-Angle Glaucoma Genetic Burden
Authors: Sekimitsu Sayuri , Xiang David , Smith Sophie Lloyd , Curran Katie , Elze Tobias , Friedman David S. , Foster Paul J. , Luo Yuyang , Pasquale Louis R. , Peto Tunde , Segrè Ayellet V. , Shweikh Yusrah , Warwick Alasdair , Zhao Yan , Wiggs Janey L. , Zebardast Nazlee ,   UK Biobank Eye and Vision Consortium, Allen Naomi , Aslam Tariq , Atan Denize , Balaskas Konstantinos , Barman Sarah , Barrett Jenny , Bishop Paul , Black Graeme , Braithwaite Tasanee , Carare Roxana , Chakravarthy Usha , Chan Michelle , Chua Sharon , Day Alexander , Desai Parul , Dhillon Bal , Dick Andrew , Doney Alexander , Egan Cathy , Ennis Sarah , Foster Paul , Fruttiger Marcus , Gallacher John , Garway-Heath David , Gibson Jane , Guggenheim Jeremy , Hammond Chris , Hardcastle Alison , Harding Simon , Hogg Ruth , Hysi Pirro , Keane Pearse , Khaw Peng Tee , Khawaja Anthony , Lascaratos Gerassimos , Littlejohns Thomas , Lotery Andrew , Luben Robert , Luthert Phil , Macgillivray Tom , Mackie Sarah , Madhusudhan Savita , Mcguinness Bernadette , Mckay Gareth , Mckibbin Martin , Moore Tony , Morgan James , O'Sullivan Eoin , Oram Richard , Owen Chris , Patel Praveen , Paterson Euan , Peto Tunde , Petzold Axel , Pontikos Nikolas , Rahi Jugnoo , Rudnicka Alicja , Sattar Naveed , Self Jay , Sergouniotis Panagiotis , Sivaprasad Sobha , Steel David , Stratton Irene , Strouthidis Nicholas , Sudlow Cathie , Sun Zihan , Tapp Robyn , Thomas Dhanes , Trucco Emanuele , Tufail Adnan , Viswanathan Ananth , Vitart Veronique , Weedon Mike , Williams Katie , Williams Cathy , Woodside Jayne , Yates Max , Zheng Yalin 
Published: August 2023

Importance

Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication.

Objective

To evaluate phenotypic features across genetic burden for POAG.

Design, Setting, and Participants

This was a cross-sectional, population-based study conducted from 2006 to 2010. Included participants were individuals from the UK Biobank aged 40 to 69 years. Individuals with non-POAG forms of glaucoma were excluded from the analysis. Data were statistically analyzed from October 2022 to January 2023.

Main Outcomes and Measures

POAG prevalence based on structural coding, self-reports, and glaucoma-related traits.

Results

Among 407 667 participants (mean [SD] age, 56.3 [8.1] years; 219 183 majority sex [53.8%]) were 14 171 POAG cases. Area under receiver operating characteristic curve for POAG detection was 0.748 in a model including polygenic risk score (PRS), age, sex, and ancestry. POAG prevalence in the highest decile of PRS was 7.4% (3005 of 40 644) vs 1.3% (544 of 40 795) in lowest decile (P &amp;lt; .001). A 1-SD increase in PRS was associated with 1.74 times higher odds of POAG (95% CI, 1.71-1.77), a 0.61-mm Hg increase in corneal-compensated intraocular pressure (IOP; 95% CI, 0.59-0.64), a −0.09-mm Hg decrease in corneal hysteresis (95% CI, −0.10 to −0.08), a 0.08-mm Hg increase in corneal resistance factor (95% CI, 0.06-0.09), and a −0.08-diopter decrease in spherical equivalent (95% CI, −0.11 to −0.07; P &amp;lt; .001 for all). A 1-SD increase in PRS was associated with a thinning of the macula-region retinal nerve fiber layer (mRNFL) of 0.14 μm and macular ganglion cell complex (GCC) of 0.26 μm (P &amp;lt; .001 for both). In the subset of individuals with fundus photographs, a 1-SD increase in PRS was associated with 1.42 times higher odds of suspicious optic disc features (95% CI, 1.19-1.69) and a 0.013 increase in cup-disc ratio (CDR; 95% CI, 0.012-0.014; P &amp;lt; .001 for both). A total of 22 of 5193 fundus photographs (0.4%) in decile 10 had disc hemorrhages, and 27 of 5257 (0.5%) had suspicious optic disc features compared with 9 of 5158 (0.2%) and 10 of 5219 (0.2%), respectively, in decile 1 (P &amp;lt; .001 for both). CDR in decile 10 was 0.46 compared with 0.41 in decile 1 (P &amp;lt; .001).

Conclusion and Relevance

Results suggest that PRS identified a group of individuals at substantially higher risk for POAG. Higher genetic risk was associated with more advanced disease, namely higher CDR and corneal-compensated IOP, thinner mRNFL, and thinner GCC. Associations with POAG PRS and corneal hysteresis and greater prevalence of disc hemorrhages were identified. These results suggest that genetic risk is an increasingly important parameter for risk stratification to consider in clinical practice.