Importance Anterior uveitis is an intraocular disease characterized by inflammation of the iris and the ciliary body and known to co-occur with autoimmune diseases. This is the largest genome-wide association study (GWAS) meta-analysis specifically for anterior uveitis to date.

Objective The purpose of this study is to define genetic factors associated with anterior uveitis through genome-wide association study.

Design, setting and participants In this GWAS meta-analysis we combined data from the FinnGen, Estonian Biobank and UK Biobank with a total of 12 205 anterior uveitis cases and 917 145 controls. We performed a phenome-wide association study to investigate associations across phenotypes and traits. We also evaluated genetic correlations of anterior uveitis.

Main outcomes and measures Genetic variants associated with anterior uveitis.

Results We identified six anterior uveitis associated loci. Genome-wide significant (p < 5 × 10−8) associations were identified for the first time at three loci (INAVA, NLRP3 and NOS2). We detected associations at three loci previously reported to be associated with uveitis (ERAP1, TNRC18 and the HLA region) and also replicated associations at two loci previously associated with acute anterior uveitis (IL23R and HDAC2-AS2). In phenome-wide association study, we further detected that lead single nucleotide polymorphism, SNPs, at three of the anterior uveitis associated loci (ERAP1, INAVA and TNRC18) are associated with other immunity-related phenotypes, including ankylosing spondylitis and inflammatory bowel disease. Additionally, we detected a moderate genetic correlation between anterior uveitis and inflammatory bowel disease (rg=0.39, p = 8 × 10−5).

Conclusions and relevance We identified six anterior uveitis associated loci including three novel loci with genome-wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune related disorders, providing a foundation for further research and potential therapeutic interventions.

The authors have declared no competing interest.

We want to acknowledge the participants and investigators of FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis Pharma AG, and Boehringer Ingelheim International GmbH. Following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/) and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious® services (https://site.fingenious.fi/en/) managed by FINBB. We want to acknowledge the participants of the Estonian Biobank for their contributions. The Estonian Genome Center GWAS analyses were performed in the High Performance Computing Center, University of Tartu. The activities of the EstBB are regulated by the Human Genes Research Act. Individual level data analysis in EstBB was carried out under ethical approval 1.1-12/1020 from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs). The work of the Estonian Genome Center, University of Tartu was funded by the Estonian Research Council Grant PRG1291, and University of Helsinki Grant VLTGI20638. This study has received funding from the Suomen Silmälääkäriyhdistys, the Silmäsäätiö Foundation, the Sokeain Ystävät Foundation, the Mary and Georg C. Ehrnrooth Foundation and the Evald ja Hilda Nissin säätiö Foundation. The funding organizations had no role in the design or conduct of this study. The authors have no conflict of interest.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

FinnGen DF10 ethics statement. Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL/2031/6.02.00/2017, THL/1101/5.05.00/2017, THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/283/6.02.00/2019, THL/1721/5.05.00/2019 and THL/1524/5.05.00/2020), Digital and population data service agency (permit numbers: VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3), the Social Insurance Institution (permit numbers: KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, KELA 134/522/2019, KELA 138/522/2019, KELA 2/522/2020, KELA 16/522/2020), Findata permit numbers THL/2364/14.02/2020, THL/4055/14.06.00/2020, THL/3433/14.06.00/2020, THL/4432/14.06/2020, THL/5189/14.06/2020, THL/5894/14.06.00/2020, THL/6619/14.06.00/2020, THL/209/14.06.00/2021, THL/688/14.06.00/2021, THL/1284/14.06.00/2021, THL/1965/14.06.00/2021, THL/5546/14.02.00/2020, THL/2658/14.06.00/2021, THL/4235/14.06.00/2021, Statistics Finland (permit numbers: TK-53-1041-17 and TK/143/07.03.00/2020 (earlier TK-53-90-20) TK/1735/07.03.00/2021, TK/3112/07.03.00/2021) and Finnish Registry for Kidney Diseases permission/extract from the meeting minutes on 4th July 2019. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 10 include: THL Biobank BB2017_55, BB2017_111, BB2018_19, BB_2018_34, BB_2018_67, BB2018_71, BB2019_7, BB2019_8, BB2019_26, BB2020_1, BB2021_65, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017, HUS/248/2020, HUS/150/2022 sections 12, 13, 14, 15, 16, 17, 18, and 23, Auria Biobank AB17-5154 and amendment #1 (August 17 2020) and amendments BB_2021-0140, BB_2021-0156 (August 26 2021, Feb 2 2022), BB_2021-0169, BB_2021-0179, BB_2021-0161, AB20-5926 and amendment #1 (April 23 2020)and it's modification (Sep 22 2021), Biobank Borealis of Northern Finland_2017_1013, 2021_5010, 2021_5018, 2021_5015, 2021_5023, 2021_5017, 2022_6001, Biobank of Eastern Finland 1186/2018 and amendment 22 section /2020, 53/2021, 13/2022, 14/2022, 15/2022, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), 8/2021, 9/2022, 10/2022, 12/2022, 20/2022, 21/2022, 22/2022, 23/2022, Central Finland Biobank 1-2017, and Terveystalo Biobank STB 2018001 and amendment 25th Aug 2020, Finnish Hematological Registry and Clinical Biobank decision 18th June 2021, Arctic biobank P0844: ARC_2021_1001.

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