Study / S921063152026-01-12
Single-cell multiome and enhancer connectome of human retinal pigment epithelium and choroid nominate causal variants in macular degeneration
Sean K. Wang, Jiaying Li, Surag Nair, Reshma Kosaraju, Yun Chen et al.
About this study
Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Genome-wide association studies (GWASs) of AMD have identified dozens of risk loci that may house disease targets. However, variants at these loci are largely noncoding, making it difficult to assess their function and whether they are causal. Here, we present a single-cell gene expression and chromatin accessibility atlas of human retinal pigment epithelium (RPE) and choroid to systematically analyze both coding and noncoding variants implicated in AMD. We employ HiChIP and activity-by-contact modeling to map enhancers in these tissues and predict cell and gene targets of risk variants. We further perform allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to functionally test variant activity in RPE cells, including in the context of complement activation. Our work nominates pathogenic variants and mechanisms in AMD and offers a rich and accessible resource for studying diseases of the RPE and choroid.
Full author list & citation
Sean K. Wang, Jiaying Li, Surag Nair, Reshma Kosaraju, Yun Chen, Yuanyuan Zhang, Anshul Kundaje, Yuwen Liu, Ningli Wang, Howard Y. Chang. Single-cell multiome and enhancer connectome of human retinal pigment epithelium and choroid nominate causal variants in macular degeneration. 2026-01-12. https://doi.org/10.1016/j.celrep.2025.116814
Experiments 1
E07315118
A focused allele-specific STARR-seq library tested reference and alternative alleles centered in 152 bp of genomic context for AMD-associated SNPs and MAPT-locus control SNPs in the human RPE cell line ARPE-19. The same input plasmid library was measured after 24 hours in four biological replicates of naïve culture and four biological replicates of complement-activated culture; the table reports the final QC-passing variant-level enhancer and allelic activity results for both conditions.