# Single-cell multiome and enhancer connectome of human retinal pigment epithelium and choroid nominate causal variants in macular degeneration

## TL;DR

This study uses multi-omic data to identify and functionally test genetic variants linked to age-related macular degeneration in human eye tissues.

## Contribution

The work introduces a comprehensive single-cell multiome atlas and enhancer connectome for studying AMD risk variants.

## Key findings

- Nearly 2,000 AMD-linked variants were evaluated, with dozens nominated as pathogenic.
- Enhancer mapping and functional testing revealed cell and gene targets of risk variants.
- Allele-specific STARR-seq confirmed variant activity in RPE cells, including during complement activation.

## Abstract

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.

Wang, Li, et al. apply a multi-omic framework to human retinal pigment epithelium and choroid, the earliest tissues affected in age-related macular degeneration. Using a combination of single-cell transcriptomics, single-cell epigenomics, enhancer mapping, and functional testing, they evaluate nearly 2,000 variants linked to this disease and nominate dozens as pathogenic.