Functional genomics in age-related macular degeneration: From genetic associations to understanding disease mechanisms

Rinki Ratnapriya; Felix Grassman; Rui Chen; Alex Hewitt; Jianhai Du; Daniel R Saban; Caroline C W Klaver; John Ash; Dwight Stambolian; Santa J Tumminia; Jiang Qian; Deeba Husain; Sudha K Iyengar; Anneke I den Hollander

doi:10.1016/j.exer.2025.110344

Functional genomics in age-related macular degeneration: From genetic associations to understanding disease mechanisms

Exp Eye Res. 2025 May:254:110344. doi: 10.1016/j.exer.2025.110344. Epub 2025 Mar 13.

Authors

Rinki Ratnapriya¹, Felix Grassman², Rui Chen³, Alex Hewitt⁴, Jianhai Du⁵, Daniel R Saban⁶, Caroline C W Klaver⁷, John Ash⁸, Dwight Stambolian⁹, Santa J Tumminia¹⁰, Jiang Qian¹¹, Deeba Husain¹², Sudha K Iyengar¹³, Anneke I den Hollander¹⁴

Affiliations

¹ Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
² Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
⁵ Department of Ophthalmology and Visual Sciences, Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, USA.
⁶ Department of Ophthalmology, Duke University School of Medicine, Durham, NC, USA; Department of Integrative Immunobiology, Duke University, Durham, NC, USA.
⁷ Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands; Institute of Molecular and Clinical Ophthalmology, University of Basel, Basel, Switzerland.
⁸ Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA.
⁹ Univeristy of Pennsylvania, USA.
¹⁰ National Eye Institute, Bethesda, MD, USA.
¹¹ Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
¹³ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹⁴ Genomics Research Center, AbbVie, North Chicago, IL, USA; Genomics Research Center, AbbVie, Cambridge, MA, USA. Electronic address: anneke.denhollander@abbvie.com.

PMID: 40089136
PMCID: PMC12048874 (available on 2026-05-01)
DOI: 10.1016/j.exer.2025.110344

Abstract

Genome-wide association studies have been remarkably successful in identifying genetic variants associated with age-related macular degeneration (AMD), demonstrating a strong genetic component largely driven by common variants. However, progress in translating these genetic findings into a deeper understanding of disease mechanisms and new therapies has been slow. Slow progress in this area can be attributed to limited knowledge of the functional impact of AMD-associated non-coding variants on gene function, the molecular mechanisms and cell types underlying disease. This review offers a comprehensive overview of functional genomics approaches to uncover the genetic, epigenetic, cellular and molecular mechanisms underlying AMD and outlines future directions for research.

Keywords: Cellular models of AMD; Gene prioritization; Gene regulation; Genome-wide association study (GWAS); Microglia; Quantitative trait loci (QTL); Village-in-a-dish.

Publication types

Review

MeSH terms

Genetic Predisposition to Disease
Genome-Wide Association Study
Genomics* / methods
Humans
Macular Degeneration* / genetics

Abstract

Publication types

MeSH terms

Grants and funding