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Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Author

Listed:
  • Andrew R. Hamel

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Wenjun Yan

    (Harvard University)

  • John M. Rouhana

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Aboozar Monovarfeshani

    (Harvard University)

  • Xinyi Jiang

    (The University of Edinburgh
    The University of Edinburgh)

  • Puja A. Mehta

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Jayshree Advani

    (National Institutes of Health)

  • Yuyang Luo

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Qingnan Liang

    (Baylor College of Medicine)

  • Skanda Rajasundaram

    (Harvard Medical School
    University of Oxford
    Imperial College London)

  • Arushi Shrivastava

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Katherine Duchinski

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT
    Harvard Medical School)

  • Sreekar Mantena

    (Massachusetts Eye and Ear
    Harvard Medical School)

  • Jiali Wang

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Tavé van Zyl

    (Harvard University
    Yale School of Medicine)

  • Louis R. Pasquale

    (Icahn School of Medicine at Mount Sinai)

  • Anand Swaroop

    (National Institutes of Health)

  • Puya Gharahkhani

    (QIMR Berghofer Medical Research Institute)

  • Anthony P. Khawaja

    (Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology)

  • Stuart MacGregor

    (QIMR Berghofer Medical Research Institute)

  • Rui Chen

    (Baylor College of Medicine)

  • Veronique Vitart

    (The University of Edinburgh)

  • Joshua R. Sanes

    (Harvard University)

  • Janey L. Wiggs

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Ayellet V. Segrè

    (Massachusetts Eye and Ear
    Harvard Medical School
    Broad Institute of Harvard and MIT)

Abstract

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Suggested Citation

  • Andrew R. Hamel & Wenjun Yan & John M. Rouhana & Aboozar Monovarfeshani & Xinyi Jiang & Puja A. Mehta & Jayshree Advani & Yuyang Luo & Qingnan Liang & Skanda Rajasundaram & Arushi Shrivastava & Kather, 2024. "Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44380-y
    DOI: 10.1038/s41467-023-44380-y
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    References listed on IDEAS

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