Systems genomics in age-related macular degeneration

Anneke I. den Hollander*, Robert F. Mullins, Luz D. Orozco, Andrew P. Voigt, Hsu Hsin Chen, Tobias Strunz, Felix Grassmann, Jonathan L. Haines, Jonas J.W. Kuiper, Santa J. Tumminia, Rando Allikmets, Gregory S. Hageman, Dwight Stambolian, Caroline C.W. Klaver, Jef D. Boeke, Hao Chen, Lee Honigberg, Suresh Katti, Kelly A. Frazer, Bernhard H.F. WeberMichael B. Gorin

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
100 Downloads (Pure)


Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.

Original languageEnglish
Article number109248
Number of pages13
JournalExperimental Eye Research
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
RFM: NIH grant EY024605 . JLH: NIH R01 grants EY022310 ; EY030614 . RA: NIH / NEI grants R01EY028203 , R01EY028954 , R01EY029315 , P30EY019007 , Foundation Fighting Blindness Program Project award PPA-1218-0751-COLU , and Unrestricted funds from the Research to Prevent Blindness (RPB) to the Department of Ophthalmology, Columbia University, New York, NY, USA. GSH: NIH ( R01 EY014800 , R24 EY017404 ), charitable donations made to the Sharon Eccles Steele Center for Translational Medicine, Voyant Biotherapeutics LLC, Perceive Biotherapeutics Inc. and an unrestricted grant from Research to Prevent Blindness , New York, NY, to the Department of Ophthalmology and Visual Sciences, University of Utah. DS: NIH R01 EY031209 and Support Sight Foundation (TSSF). KAF: NIH grant R01EY031663 . MBG: Harold and Pauline Price Foundation , unrestricted grant to the Dept of Ophthalmology UCLA by Research to Prevent Blindness, NY NY, and The William & Margaret Fern Holmes Family Foundation .

Publisher Copyright: © 2022 The Author(s)


Dive into the research topics of 'Systems genomics in age-related macular degeneration'. Together they form a unique fingerprint.

Cite this