Performance of Polygenic Risk Scores for Primary Open-Angle Glaucoma in Populations of African Descent
Authors: Chang-Wolf Jennifer M. , Kinzy Tyler G. , Driessen Sjoerd J. , Cruz Lauren A. , Iyengar Sudha K. , Peachey Neal S. , Aung Tin , Khor Chiea Chuen , Williams Susan E. , Ramsay Michele , Olawoye Olusola , Ashaye Adeyinka , Klaver Caroline C. W. , Hauser Michael A. , Thiadens Alberta A. H. J. , Cooke Bailey Jessica N. , Bonnemaijer Pieter W. M. ,   Genetics in Glaucoma Patients of African Descent (GIGA) Study GroupGenetics of Glaucoma in People of African Descent (GGLAD) Study GroupMillion Veteran Program (MVP), Sanywia Anna J. , Cook Colin , Hassan Hassan G. , Kanyaro Neema , Ntomoka Cyprian , Allingham R.R. , van der Heide Carly J , Taylor Kent D , Rotter Jerome I , Wang Shih-Hsiu J , ABDULLAHI Sadiq M , Abu-Amero Khaled K. , Anderson Michael G , Akafo Stephen , ALHASSAN Mahmoud B , Asimadu Ifeoma , Ayyagari Radha , BAKAYOKO Seydou , BIANGOUP NYAMSI Prisca , Bowden Donald W , Bromley William C , Budenz Donald L , Carmichael Trevor R , Challa Pratap , Chen Yii-Der Ida , Chuka-Okosa Chimdi M , Costa Vital Paulino , Cruz Dianne A , DuBiner Harvey , Ervin JF , Feldman Robert M , Flamme-Wiese Miles , Gaasterland Douglas E , Garnai Sarah , Girkin Christopher A , GUIROU Nouhoum , Guo Xiuqing , Haines Jonathan , Hammond CJ , Herndon Leon , Hoffmann Thomas J , Hulette Christine M , Hydara Abba , Igo Jr. Robert P , Jorgenson Eric , KABWE Joyce , KILANGALANGA Ngoy Janvier , Kizor-Akaraiwe Nkiru , Kuchtey Rachel W , LAMARI Hasnaa , Li Zheng , Liebmann Jeffrey M , Liu Yutao , Loos Ruth JF , Melo Monica B , Moroi Sayoko E , Msosa Joseph M , Mullins Robert F , Nadkarni Girish , NAPO Abdoulaye , Ng Maggie C.Y. , Nunes Hugo Freire , Obeng-Nyarkoh Ebenezer , Okeke Anthony , Okeke Suhanya , OLANIYI Olusegun , Oliveira Mariana Borges , Pasquale Louis R , Perez-Grossmann Rodolfo A. , Pericak-Vance Margaret A , Qin XJ , RESNIKOFF Serge , Richards Julia E , Schimiti Rui Barroso , Sim Kar Seng , Sponsel William E , Svidnicki Paulo Vinícius , Uche Nkechinyere J , van Duijn CM , Vasconcellos José Paulo Cabral de , Wiggs Janey L , Zangwill Linda M , Risch Neil , Milea Dan , Weinreb Robert N , Ashley-Koch Allison E , Fingert John H , Aslan Mihaela , Antonelli M , de Asis M , Bauer MS , Brophy Mary , Concato John , Cunningham F , Freedman R , Gaziano Michael , Gleason Theresa , Harvey Philip , Huang Grant , Kelsoe J , Kosten Thomas , Lehner T , Lohr JB , Marder SR , Miller P , O Leary Timothy , Patterson T , Peduzzi P , Przygodski Ronald , Siever Larry , Sklar P , Strakowski S , Zhao Hongyu , Fanous Ayman , Farwell W , Malhorta A , Mane S , Palacios P , Bigdeli Tim , Corsey M , Zaluda L , Johnson Juanita , Sueiro Melyssa , Cavaliere D , Jeanpaul V , Maffucci Alysia , Mancini L , Deen J , Muldoon G , Whitbourne Stacey , Canive J , Adamson L , Calais L , Fuldauer G , Kushner R , Toney G , Lackey M , Mank A , Mahdavi N , Villarreal G , Muly EC , Amin F , Dent M , Wold J , Fischer B , Elliott A , Felix C , Gill G , Parker PE , Logan C , McAlpine J , DeLisi LE , Reece SG , Hammer MB , Agbor‐Tabie D , Goodson W , Aslam M , Grainger M , Richtand Neil , Rybalsky Alexander , Al Jurdi R , Boeckman E , Natividad T , Smith D , Stewart M , Torres S , Zhao Z , Mayeda A , Green A , Hofstetter J , Ngombu S , Scott MK , Strasburger A , Sumner J , Paschall G , Mucciarelli J , Owen R , Theus S , Tompkins D , Potkin SG , Reist C , Novin M , Khalaghizadeh S , Douyon Richard , Kumar Nita , Martinez Becky , Sponheim SR , Bender TL , Lucas HL , Lyon AM , Marggraf MP , Sorensen LH , Surerus CR , Sison C , Amato J , Johnson DR , Pagan‐Howard N , Adler LA , Alerpin S , Leon T , Mattocks KM , Araeva N , Sullivan JC , Suppes T , Bratcher K , Drag L , Fischer EG , Fujitani L , Gill S , Grimm D , Hoblyn J , Nguyen T , Nikolaev E , Shere L , Relova R , Vicencio A , Yip M , Hurford I , Acheampong S , Carfagno G , Haas GL , Appelt C , Brown E , Chakraborty B , Kelly E , Klima G , Steinhauer S , Hurley RA , Belle R , Eknoyan D , Johnson K , Lamotte J , Granholm E , Bradshaw K , Holden J , Jones RH , Le T , Molina IG , Peyton M , Ruiz I , Sally L , Tapp A , Devroy S , Jain V , Kilzieh N , Maus L , Miller K , Pope H , Wood A , Meyer E , Givens P , Hicks PB , Justice S , McNair K , Pena JL , Tharp DF , Davis L , Ban M , Cheatum L , Darr P , Grayson W , Munford J , Whitfield B , Wilson E , Melnikoff SE , Schwartz BL , Tureson MA , D Souza D , Forselius K , Ranganathan M , Rispoli L , Sather M , Colling C , Haakenson C , Kruegar D , Muralidhar Sumitra , Ramoni Rachel , Breeling Jim , Chang Kyong‐Mi , O Donnell Christopher , Tsao Philip , Moser Jennifer , Brewer Jessica , Warren Stuart , Argyres Dean , Stevens Brady , Humphries Donald , Do Nhan , Shayan Shahpoor , Nguyen Xuan‐Mai , Pyarajan Saiju , Cho Kelly , Hauser Elizabeth , Sun Yan , Wilson Peter , McArdle Rachel , Dellitalia Louis , Harley John , Whittle Jeffrey 
Published: November 2024

Importance

Primary open-angle glaucoma (POAG) polygenic risk scores (PRSs) continue to be evaluated in primarily European-ancestry populations despite higher prevalence and worse outcomes in African-ancestry populations.

Objective

To evaluate how established POAG PRSs perform in African-ancestry samples from the Genetics in Glaucoma Patients of African Descent (GIGA), Genetics of Glaucoma in Individuals of African Descent (GGLAD), and Million Veteran Program (MVP) datasets and compare these with European-ancestry samples.

Design, Setting, and Participants

This was a multicenter, cross-sectional study of POAG cases and controls from Tanzania, South Africa, Nigeria, Ghana, and the US. Included were individuals of African descent from South Africa and Tanzania from the GIGA dataset; individuals of African descent from Ghana, Nigeria, and the US from the GGLAD dataset; and individuals of African or European descent from the US in the MVP dataset. Data were analyzed from January 2022 to July 2023.

Exposures

Three PRSs derived from large meta-analyses of European and Asian populations, namely Gharahkhani et al (Gharahkhani PRS), Han et al (Han PRS), and Craig et al (Craig PRS).

Main Outcomes and Measures

Odds ratios (ORs) for POAG risk stratification comparing the highest and lowest quintiles; area under the receiver operating characteristic curve (AUROC), and liability coefficient of determination (R2) for the addition of PRS to a baseline of age, sex, and first 5 principal components.

Results

A total of 11 673 cases and 66 432 controls were included in this study across 7 ancestral groups. Mean (SD) age of the total participants was 76.9 (8.7) years, with 74 304 males (95.1%). The following were included in each dataset: GIGA (663 cases, 476 controls), GGLAD (1471 cases, 1482 controls), and MVP (9559 cases, 64 474 controls). Increases in ORs were found for the highest POAG risk quintile ranging from an OR of 1.68 (95% CI, 1.17-2.43) in Ghanaians to 7.05 (95% CI, 2.73-19.6) in the South African multiple ancestry group (which derives from at least 5 distinct ancestral groups: Khoisan, Bantus, Europeans, Indians, and Southeast Asians) with the Gharahkhani PRS. The Han PRS showed OR increases for the highest POAG risk quintile ranging from 2.27 (95% CI, 1.49-3.47) in African American individuals in the GGLAD dataset to 7.24 (95% CI, 6.47-8.12) in Europeans. The Craig PRS predicted OR increases in the highest quintile for all groups ranging from 1.51 (95% CI, 1.05-2.18) in Ghanaians to 6.31 (95% CI, 5.67-7.04) in Europeans. However, AUROC and R2 increases above baseline were lower for all African-ancestry compared with European-ancestry groups in the 3 tested PRSs.

Conclusions and Relevance

In this cross-sectional study, despite some improvements in OR-based risk stratification using the Gharahkhani PRSs, Han PRSs, and Craig PRSs, consistently lower improvements in AUROC and R2 for African-ancestry compared with European-ancestry groups highlight the need for risk prediction models tailored to diverse populations.