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A large meta-analysis identifies genes associated with anterior uveitis

Author

Listed:
  • Sahar Gelfman

    (Regeneron Genetics Center)

  • Arden Moscati

    (Regeneron Genetics Center)

  • Santiago Mendez Huergo

    (Regeneron Pharmaceuticals)

  • Rujin Wang

    (Regeneron Genetics Center)

  • Veera Rajagopal

    (Regeneron Genetics Center)

  • Neelroop Parikshak

    (Regeneron Genetics Center)

  • Vijay Kumar Pounraja

    (Regeneron Genetics Center)

  • Esteban Chen

    (Regeneron Genetics Center)

  • Michelle Leblanc

    (Regeneron Genetics Center)

  • Ralph Hazlewood

    (Regeneron Pharmaceuticals)

  • Jan Freudenberg

    (Regeneron Genetics Center)

  • Blerta Cooper

    (Regeneron Pharmaceuticals)

  • Ann J. Ligocki

    (Regeneron Pharmaceuticals)

  • Charles G. Miller

    (Regeneron Pharmaceuticals)

  • Tavé Zyl

    (Regeneron Pharmaceuticals)

  • Jonathan Weyne

    (Regeneron Pharmaceuticals)

  • Carmelo Romano

    (Regeneron Pharmaceuticals)

  • Botir Sagdullaev

    (Regeneron Pharmaceuticals)

  • Olle Melander

    (Lund University)

  • Aris Baras

    (Regeneron Genetics Center)

  • Eli A. Stahl

    (Regeneron Genetics Center)

  • Giovanni Coppola

    (Regeneron Genetics Center)

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.

Suggested Citation

  • Sahar Gelfman & Arden Moscati & Santiago Mendez Huergo & Rujin Wang & Veera Rajagopal & Neelroop Parikshak & Vijay Kumar Pounraja & Esteban Chen & Michelle Leblanc & Ralph Hazlewood & Jan Freudenberg , 2023. "A large meta-analysis identifies genes associated with anterior uveitis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43036-1
    DOI: 10.1038/s41467-023-43036-1
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    References listed on IDEAS

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    1. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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