QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration
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...
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46063-8 |
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| author | Jayshree Advani Puja A. Mehta Andrew R. Hamel Sudeep Mehrotra Christina Kiel Tobias Strunz Ximena Corso-Díaz Madeline Kwicklis Freekje van Asten Rinki Ratnapriya Emily Y. Chew Dena G. Hernandez Sandra R. Montezuma Deborah A. Ferrington Bernhard H. F. Weber Ayellet V. Segrè Anand Swaroop |
| author_facet | Jayshree Advani Puja A. Mehta Andrew R. Hamel Sudeep Mehrotra Christina Kiel Tobias Strunz Ximena Corso-Díaz Madeline Kwicklis Freekje van Asten Rinki Ratnapriya Emily Y. Chew Dena G. Hernandez Sandra R. Montezuma Deborah A. Ferrington Bernhard H. F. Weber Ayellet V. Segrè Anand Swaroop |
| author_sort | Jayshree Advani |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8d47fc27aef84583ace1428d94cd4bdd |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8d47fc27aef84583ace1428d94cd4bdd2025-02-02T12:31:04ZengNature PortfolioNature Communications2041-17232024-03-0115112010.1038/s41467-024-46063-8QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degenerationJayshree Advani0Puja A. Mehta1Andrew R. Hamel2Sudeep Mehrotra3Christina Kiel4Tobias Strunz5Ximena Corso-Díaz6Madeline Kwicklis7Freekje van Asten8Rinki Ratnapriya9Emily Y. Chew10Dena G. Hernandez11Sandra R. Montezuma12Deborah A. Ferrington13Bernhard H. F. Weber14Ayellet V. Segrè15Anand Swaroop16Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and EarOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and EarOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and EarInstitute of Human Genetics, University of RegensburgInstitute of Human Genetics, University of RegensburgNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthDivision of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of HealthLaboratory of Neurogenetics, National Institute of Aging, National Institutes of HealthDepartment of Ophthalmology and Visual Neurosciences, University of MinnesotaDepartment of Ophthalmology and Visual Neurosciences, University of MinnesotaInstitute of Human Genetics, University of RegensburgOcular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and EarNeurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of HealthAbstract 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.https://doi.org/10.1038/s41467-024-46063-8 |
| spellingShingle | Jayshree Advani Puja A. Mehta Andrew R. Hamel Sudeep Mehrotra Christina Kiel Tobias Strunz Ximena Corso-Díaz Madeline Kwicklis Freekje van Asten Rinki Ratnapriya Emily Y. Chew Dena G. Hernandez Sandra R. Montezuma Deborah A. Ferrington Bernhard H. F. Weber Ayellet V. Segrè Anand Swaroop QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration Nature Communications |
| title | QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration |
| title_full | QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration |
| title_fullStr | QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration |
| title_full_unstemmed | QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration |
| title_short | QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration |
| title_sort | qtl mapping of human retina dna methylation identifies 87 gene epigenome interactions in age related macular degeneration |
| url | https://doi.org/10.1038/s41467-024-46063-8 |
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