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

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

doi:10.1038/s41467-024-46063-8

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

Nat Commun. 2024 Mar 4;15(1):1972. doi: 10.1038/s41467-024-46063-8.

Authors

Jayshree Advani¹, Puja A Mehta^{2

3

4}, Andrew R Hamel^{2

3

4}, Sudeep Mehrotra^{2

3

4}, Christina Kiel⁵, Tobias Strunz⁵, Ximena Corso-Díaz¹, Madeline Kwicklis¹, Freekje van Asten¹, Rinki Ratnapriya¹, Emily Y Chew⁶, Dena G Hernandez⁷, Sandra R Montezuma⁸, Deborah A Ferrington^{8

9}, Bernhard H F Weber^{5

10}, Ayellet V Segrè^{11

12

13}, Anand Swaroop¹⁴

Affiliations

¹ Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
² Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA.
³ Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
⁶ Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA.
⁸ Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.
⁹ Doheny Eye Institute, Pasadena, CA, USA.
¹⁰ Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.
¹¹ Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, MA, USA. ayellet_segre@meei.harvard.edu.
¹² Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. ayellet_segre@meei.harvard.edu.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. ayellet_segre@meei.harvard.edu.
¹⁴ Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. swaroopa@nei.nih.gov.

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.

MeSH terms

DNA Methylation* / genetics
Epigenesis, Genetic
Epigenome
Humans
Macular Degeneration* / genetics
Retina

Abstract

MeSH terms

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