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QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration

Author

Listed:
  • Jayshree Advani

    (National Institutes of Health)

  • Puja A. Mehta

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

  • Andrew R. Hamel

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

  • Sudeep Mehrotra

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

  • Christina Kiel

    (University of Regensburg)

  • Tobias Strunz

    (University of Regensburg)

  • Ximena Corso-Díaz

    (National Institutes of Health)

  • Madeline Kwicklis

    (National Institutes of Health)

  • Freekje Asten

    (National Institutes of Health)

  • Rinki Ratnapriya

    (National Institutes of Health)

  • Emily Y. Chew

    (National Institutes of Health)

  • Dena G. Hernandez

    (National Institute of Aging, National Institutes of Health)

  • Sandra R. Montezuma

    (University of Minnesota)

  • Deborah A. Ferrington

    (University of Minnesota
    Doheny Eye Institute)

  • Bernhard H. F. Weber

    (University of Regensburg
    University Hospital Regensburg)

  • Ayellet V. Segrè

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

  • Anand Swaroop

    (National Institutes of Health)

Abstract

DNA methylation provides a crucial epigenetic mark linking genetic variations to environmental influence. We have analyzed array-based DNA methylation profiles of 160 human retinas with co-measured RNA-seq and >8 million genetic variants, uncovering sites of genetic regulation in cis (37,453 methylation quantitative trait loci and 12,505 expression quantitative trait loci) and 13,747 DNA methylation loci affecting gene expression, with over one-third specific to the retina. Methylation and expression quantitative trait loci show non-random distribution and enrichment of biological processes related to synapse, mitochondria, and catabolism. Summary data-based Mendelian randomization and colocalization analyses identify 87 target genes where methylation and gene-expression changes likely mediate the genotype effect on age-related macular degeneration. Integrated pathway analysis reveals epigenetic regulation of immune response and metabolism including the glutathione pathway and glycolysis. Our study thus defines key roles of genetic variations driving methylation changes, prioritizes epigenetic control of gene expression, and suggests frameworks for regulation of macular degeneration pathology by genotype–environment interaction in retina.

Suggested Citation

  • Jayshree Advani & Puja A. Mehta & Andrew R. Hamel & Sudeep Mehrotra & Christina Kiel & Tobias Strunz & Ximena Corso-Díaz & Madeline Kwicklis & Freekje Asten & Rinki Ratnapriya & Emily Y. Chew & Dena G, 2024. "QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46063-8
    DOI: 10.1038/s41467-024-46063-8
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    References listed on IDEAS

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    1. Olivier Delaneau & Halit Ongen & Andrew A. Brown & Alexandre Fort & Nikolaos I. Panousis & Emmanouil T. Dermitzakis, 2017. "A complete tool set for molecular QTL discovery and analysis," Nature Communications, Nature, vol. 8(1), pages 1-7, August.
    2. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    3. Xiaoquan Wen & Roger Pique-Regi & Francesca Luca, 2017. "Integrating molecular QTL data into genome-wide genetic association analysis: Probabilistic assessment of enrichment and colocalization," PLOS Genetics, Public Library of Science, vol. 13(3), pages 1-25, March.
    4. Nick Patterson & Alkes L Price & David Reich, 2006. "Population Structure and Eigenanalysis," PLOS Genetics, Public Library of Science, vol. 2(12), pages 1-20, December.
    5. Claire Marchal & Nivedita Singh & Zachary Batz & Jayshree Advani & Catherine Jaeger & Ximena Corso-Díaz & Anand Swaroop, 2022. "High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Yang Wu & Jian Zeng & Futao Zhang & Zhihong Zhu & Ting Qi & Zhili Zheng & Luke R. Lloyd-Jones & Riccardo E. Marioni & Nicholas G. Martin & Grant W. Montgomery & Ian J. Deary & Naomi R. Wray & Peter M., 2018. "Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    7. Teri A. Manolio & Francis S. Collins & Nancy J. Cox & David B. Goldstein & Lucia A. Hindorff & David J. Hunter & Mark I. McCarthy & Erin M. Ramos & Lon R. Cardon & Aravinda Chakravarti & Judy H. Cho &, 2009. "Finding the missing heritability of complex diseases," Nature, Nature, vol. 461(7265), pages 747-753, October.
    8. Mathieu Lemire & Syed H.E. Zaidi & Maria Ban & Bing Ge & Dylan Aïssi & Marine Germain & Irfahan Kassam & Mike Wang & Brent W. Zanke & France Gagnon & Pierre-Emmanuel Morange & David-Alexandre Trégouët, 2015. "Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    9. Zhihong Zhu & Zhili Zheng & Futao Zhang & Yang Wu & Maciej Trzaskowski & Robert Maier & Matthew R. Robinson & John J. McGrath & Peter M. Visscher & Naomi R. Wray & Jian Yang, 2018. "Causal associations between risk factors and common diseases inferred from GWAS summary data," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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