A large meta-analysis identifies genes associated with anterior uveitis
Authors: Gelfman Sahar , Moscati Arden , Huergo Santiago Mendez , Wang Rujin , Rajagopal Veera , Parikshak Neelroop , Pounraja Vijay Kumar , Chen Esteban , Leblanc Michelle , Hazlewood Ralph , Freudenberg Jan , Cooper Blerta , Ligocki Ann J. , Miller Charles G. , Van Zyl Tavé , Weyne Jonathan , Romano Carmelo , Sagdullaev Botir , Melander Olle , Baras Aris ,   Regeneron Genetics Center, Zhang Aaron , Mansfield Adam J. , Locke Adam , Pandey Aditeya , Campos Adrian , Ghosh Arkopravo , Gorovits Alexander , Lopez Alexander , Hawes Alicia , Fenney Alison , Averitt Amelia , Joshi Amit , Damask Amy , Bunyea Andrew , Ziyatdinov Andrey , Pandit Anita , Perez-Beals Ann , Alkelai Anna , Marcketta Anthony , Baldassari Antoine , Ayer Ariane , Gilly Arthur , Rasool Ayesha , Guvenek Aysegul , Geraghty Benjamin , Sultan Benjamin , Palmer William , Ye Bin , Zhang Blair , Boutkov Boris , Hobbs Brian , Forsythe Caitlin , Sidore Carlo , Paulding Charles , Wang Chenggu , Beechert Christina , Gillies Christopher , Zhang Chuanyi , Willer Cristen J. , Li Dadong , Sharma Deepika , Stahl Eli , Austin Eliot , Jorgenson Eric , Brian Erin D. , Mayerhofer Ernst , Edelstein Evan , Maxwell Evan K. , Tzoneva Gannie , Hindy George , Mitra George , Solari Gina , Eom Gisu , Du Hang , Khiabanian Hossein , Kosmicki Jack , Otto Jacqueline , Hernandez Jaimee , Clauer Janice , Mighty Jason , Staples Jeffrey C. , Rico-Varela Jennifer , Brown Jessie , He Jing , Zhang Jingning , Revez Joana , Hankins Jody , Mbatchou Joelle , Rivera-Picart Johannie , Silver John , Bovijn Jonas , Marchini Jonathan , Ross Jonathan , Bras Jose , Herman Joseph , Backman Joshua , Guan Ju , Rodriguez-Flores Juan , Mower Justin , Landheer Karl , Sun Kathie , Burch Kathy , Sosina Kayode , Manoochehri Kia , Skead Kimberly , Punuru Krishna Pawan , Guevara Kristy , Wu Kuan-Han , Watanabe Kyoko , Zhang Lance , Cremona Laura M. , Gurski Lauren , Chen Lei , Ganel Liron , Sun Luanluan , Habegger Lukas , Pradhan Manasi , Kapoor Manav , Ferreira Manuel Allen Revez , Jones Marcus B. , Padilla Maria Sotiropoulos , Suciu Maria Cristina , Ghoussaini Maya , Haas Mary , Lattari Michael , Kessler Michael , LeBlanc Michelle G. , Pagan Michelle , Tang Mira , Riaz Moeen , Nafde Mona , Sarwar Mudasar , Rana Nadia , Lin Nan , Verweij Niek , Banerjee Nilanjana , Nishtala Nirupama , Krasheninina Olga , Delaneau Oliver , Sosina Olukayode , Akbari Parsa , Dornbos Peter , VandeHaar Peter , Challa Prathyusha , Nakka Priyanka , Schwartz Randi , Reynoso Raymond , Panea Razvan , Schiavo Ricardo , Guerreiro Rita , Lanche Rouel , Vedantam Sailaja , Martinez Salvador Romero , Choi Sam , Zarate Samantha , Malhotra Sameer , Hart Samuel , Sreeram Sanjay , Wolf Sarah E. , Graham Sarah , Vrieze Scott , O’Keeffe Sean , Yu Sean , Gaynor Sheila , Alvarez Silvia , Balasubramanian Suganthi , Gokhale Sujit , Siceron Sunilbe , Bao Suying , De Tanima , Thornton Timothy , Polanco Tommy , Joseph Tyler , Zavala Valentina , Kumar Vijay , Mahajan Vrushali , Salerno William J. , Bai Xiaodong , Zou Yuxin , Gu Zhenhua , Ferrando Adolfo , Shuldiner Alan , Deubler Andrew , Economides Aris , Abecasis Gonçalo Rocha , Reid Jeffrey G. , Overton John D. , Siminovitch Katherine , Lotta Luca A. , Mitnaul Lyndon J. , Cantor Michael , Stahl Eli A. , Coppola Giovanni 
Published: November 2023

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.