{"doi":"10.1073/pnas.2215005120","title":"CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with <i>ARMS2/HTRA1</i> -related AMD","abstract":"Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G&gt;T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion–deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 ( ARMS2 ) gene, and the G512A (G&gt;A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 ( HTRA1 ) promoter. The fourth variant is Y402H complement factor H ( CFH ), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":342616,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9468,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":916490,"name":"Laura A. Jenny","orcid":"0000-0001-8959-7074","position":1,"is_corresponding":false},{"id":161909,"name":"Yong-Shi Li","orcid":null,"position":2,"is_corresponding":false},{"id":868637,"name":"Xuan Cui","orcid":"0000-0003-2114-5973","position":3,"is_corresponding":false},{"id":713933,"name":"Yang Kong","orcid":"0000-0003-3925-5572","position":4,"is_corresponding":false},{"id":706436,"name":"Yao Li","orcid":"0000-0001-8402-3178","position":5,"is_corresponding":false},{"id":263802,"name":"Janet R. Sparrow","orcid":"0000-0001-7448-5950","position":6,"is_corresponding":false},{"id":299097,"name":"Stephen H. Tsang","orcid":"0000-0001-9082-2427","position":7,"is_corresponding":false},{"id":934884,"name":"Ya-Ju Chang","orcid":"0000-0001-9704-5448","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T01:11:17.288563Z","pmid":"37126685","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}