A large meta-analysis identifies genes associated with anterior uveitis
Sahar Gelfman, Arden Moscati, Santiago Méndez Huergo, Rujin Wang, Veera M. Rajagopal, Neelroop Parikshak, Vijay Kumar Pounraja, Esteban Chen, Michelle G. LeBlanc, Ralph J. Hazlewood, Jan Freudenberg, Blerta Cooper, Ann J. Ligocki, Charles G. Miller, Tavé van Zyl, Jonathan Weyne, Carmelo Romano, Botir T. Sagdullaev, Olle Melander, Aris Baras, Aaron Zhang, Adam J. Mansfield, Adam E. Locke, Aditeya Pandey, Adrián I. Campos, Arkopravo Ghosh, Alexander Gorovits, Alexander Lopez, Alicia Hawes, Alison Fenney, Amelia Averitt, Amit D. Joshi, Amy Damask, Andrew Bunyea, Andrey Ziyatdinov, Anita Pandit, Ann Perez-Beals, Anna Alkelai, Anthony Marcketta, Antoine Baldassari, Ariane Ayer, Arthur Gilly, Ayesha Rasool, Ayşegül Güvenek, Benjamin Geraghty, Benjamin Sultan, William Palmer, Bin Ye, Blair Zhang, Boris Boutkov, Brian D. Hobbs, Caitlin Forsythe, Carlo Sidore, Charles Paulding, Chenggu Wang, Christina Beechert, Christopher E. Gillies, Chuanyi Zhang, Cristen J. Willer, Dadong Li, Deepika Sharma, Eli A. Stahl, Eliot Austin, Eric Jorgenson, Erin D. Brian, Ernst Mayerhofer, Evan Edelstein, Evan K. Maxwell, Gannie Tzoneva, George Hindy, George Mitra, Gina Solari, Gisu Eom, Hang Du, Hossein Khiabanian, Jack A. Kosmicki, Jacqueline M. Otto, Jaimee Hernandez, Janice Clauer, Jason Mighty, Jeffrey Staples, Jennifer Rico‐Varela, Jessie Brown, Jing He, Jingning Zhang, Joana Revez, Jody Hankins, Joelle Mbatchou, Johannie Rivera-Picart, John Silver, Jonas Bovijn, Jonathan Marchini, Jonathan Ross, José Brás, Joseph Herman, Joshua Backman, Ju Guan, Juan L. Rodríguez-Flores, Justin Mower, Karl Landheer
Abstract
Anterior Uveitis (AU) is the inflammation of the anterior part of the eye, the iris and ciliary body and is strongly associated with HLA-B*27. We report AU exome sequencing results from eight independent cohorts consisting of 3,850 cases and 916,549 controls. We identify common genome-wide significant loci in HLA-B (OR = 3.37, p = 1.03e-196) and ERAP1 (OR = 0.86, p = 1.1e-08), and find IPMK (OR = 9.4, p = 4.42e-09) and IDO2 (OR = 3.61, p = 6.16e-08) as genome-wide significant genes based on the burden of rare coding variants. Dividing the cohort into HLA-B*27 positive and negative individuals, we find ERAP1 haplotype is strongly protective only for B*27-positive AU (OR = 0.73, p = 5.2e-10). Investigation of B*27-negative AU identifies a common signal near HLA-DPB1 (rs3117230, OR = 1.26, p = 2.7e-08), risk genes IPMK and IDO2, and several additional candidate risk genes, including ADGFR5, STXBP2, and ACHE. Taken together, we decipher the genetics underlying B*27-positive and -negative AU and identify rare and common genetic signals for both subtypes of disease.