Importance Allergic conjunctivitis, a common presentation of allergy, co-occurs frequently with allergic rhinitis, atopic eczema and asthma. Despite its high prevalence, the genetic factors contributing to allergic conjunctivitis have not been characterized in detail.

Objective We aimed to characterize genetic factors associated with allergic conjunctivitis both in relation to and independent of systemic atopic or allergic conditions through genome-wide association study (GWAS) meta-analysis.

Design, setting and participants We performed a GWAS meta-analysis of allergic conjunctivitis utilizing data from FinnGen, the Estonian biobank and the UK biobank. In total 45 734 cases with allergic conjunctivitis and 1 084 159 controls were included. To get insights into allergic conjunctivitis-associated loci, we conducted a phenome-wide association study, performed pathway and enrichment analyses, and assessed genetic correlations with other phenotypes.

Main outcomes and measures Genetic variants associated with allergic conjunctivitis.

Results Genome-wide significant (p < 5 × 10-8) associations were identified for allergic conjunctivitis at 34 loci, many of which had not been reported to associate with allergic conjunctivitis before. Many of the associated loci included genes involved in immunology and allergy-related conditions, e.g., ID2 (OR = 0.94, p = 2.5 × 10-15) and TSLP (OR = 1.06, p = 2.5 × 10-14). Several loci associated with allergic conjunctivitis were also associated with other allergic health conditions, such as asthma, allergic rhinitis and eczema. Three loci (EIF2AK2, RANBP2, NFAT5) had no previous association to allergy-related phenotypes. In pathway analysis, we detected that allergic conjunctivitis is associated with pathways related to neuroinflammation, immune responses and cytokine signaling, including those involved in T cell activation and differentiation. We detected an enrichment of genes associated with immune-related biological processes such as cytokine production and inflammatory response. Allergic conjunctivitis was genetically correlated with 27 phenotypes, including, e.g., doctor diagnosed hay fever or allergic rhinitis (rg=0.82).

Conclusions and relevance We identified 34 allergic conjunctivitis associated loci, majority of which were involved in immunology and allergy-related conditions. Our findings underline the central role of inflammation-related genes in genetic predisposition to allergic conjunctivitis and advance the overall understanding of its genetic background.

The authors have declared no competing interest.

The work of the Estonian Genome Center, University of Tartu was funded by the Estonian Research Council Grant PRG1291. This study has received funding from Oulu University Hospital VTR funding, the Silmasaatio Foundation, Suomen Laaketieteen Saatio Foundation and the Mary and Georg C. Ehrnrooth 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.

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

Study 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 11 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/430/2021 S28, S29, HUS/150/2022 S12, S13, S14, S15, S16, S17, S18, S23, S58, S59, HUS/128/2023 S18, 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 modifications (Sep 22 2021), BB_2022-0262, BB_2022-0256, Biobank Borealis of Northern Finland_2017_1013, 2021_5010, 2021_5010 Amendment, 2021_5018, 2021_5018 Amendment, 2021_5015, 2021_5015 Amendment, 2021_5015 Amendment_2, 2021_5023, 2021_5023 Amendment, 2021_5023 Amendment_2, 2021_5017, 2021_5017 Amendment, 2022_6001, 2022_6001 Amendment, 2022_6006 Amendment, 2022_6006 Amendment, 2022_6006 Amendment_2, BB22-0067, 2022_0262, 2022_0262 Amendment, Biobank of Eastern Finland 1186/2018 and amendment 22S/2020, 53S/2021, 13S/2022, 14S/2022, 15S/2022, 27S/2022, 28S/2022, 29S/2022, 33S/2022, 35S/2022, 36S/2022, 37S/2022, 39S/2022, 7S/2023, 32S/2023, 33S/2023, 34S/2023, 35S/2023, 36S/2023, 37S/2023, 38S/2023, 39S/2023, 40S/2023, 41S/2023, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), BB2021-0140 8S/2021, 9S/2021, S9/2022, S10/2022, S12/2022, 13S/2022, S20/2022, S21/2022, S22/2022, S23/2022, 28S/2022, 29S/2022, 30S/2022, 31S/2022, 32S/2022, 38S/2022, 40S/2022, 42S/2022, 1S/2023, Central Finland Biobank 1-2017, BB_2021-0161, BB_2021-0169, BB_2021-0179, BB_2021-0170, BB_2022-0256, BB_2022-0262, BB22-0067, Decision allowing to continue data processing until 31st Aug 2024 for projects: BB_2021-0179, BB22-0067,BB_2022-0262, BB_2021-0170, BB_2021-0164, BB_2021-0161, and BB_2021-0169, 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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