一种系统生物学方法揭示了年龄相关性黄斑变性的新疾病机制。
A systems biology approach uncovers novel disease mechanisms in age-related macular degeneration.
作者信息
Orozco Luz D, Owen Leah A, Hofmann Jeffrey, Stockwell Amy D, Tao Jianhua, Haller Susan, Mukundan Vineeth T, Clarke Christine, Lund Jessica, Sridhar Akshayalakshmi, Mayba Oleg, Barr Julie L, Zavala Rylee A, Graves Elijah C, Zhang Charles, Husami Nadine, Finley Robert, Au Elizabeth, Lillvis John H, Farkas Michael H, Shakoor Akbar, Sherva Richard, Kim Ivana K, Kaminker Joshua S, Townsend Michael J, Farrer Lindsay A, Yaspan Brian L, Chen Hsu-Hsin, DeAngelis Margaret M
机构信息
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, The University of Utah, Salt Lake City, UT 84132, USA.
出版信息
Cell Genom. 2023 Apr 18;3(6):100302. doi: 10.1016/j.xgen.2023.100302. eCollection 2023 Jun 14.
Age-related macular degeneration (AMD) is a leading cause of blindness, affecting 200 million people worldwide. To identify genes that could be targeted for treatment, we created a molecular atlas at different stages of AMD. Our resource is comprised of RNA sequencing (RNA-seq) and DNA methylation microarrays from bulk macular retinal pigment epithelium (RPE)/choroid of clinically phenotyped normal and AMD donor eyes (n = 85), single-nucleus RNA-seq (164,399 cells), and single-nucleus assay for transposase-accessible chromatin (ATAC)-seq (125,822 cells) from the retina, RPE, and choroid of 6 AMD and 7 control donors. We identified 23 genome-wide significant loci differentially methylated in AMD, over 1,000 differentially expressed genes across different disease stages, and an AMD Müller state distinct from normal or gliosis. Chromatin accessibility peaks in genome-wide association study (GWAS) loci revealed putative causal genes for AMD, including and . Our systems biology approach uncovered molecular mechanisms underlying AMD, including regulators of WNT signaling, and , as mechanistic players in disease.
年龄相关性黄斑变性（AMD）是导致失明的主要原因，全球有2亿人受其影响。为了确定可作为治疗靶点的基因，我们创建了一个AMD不同阶段的分子图谱。我们的资源包括来自临床表型正常和AMD供体眼睛（n = 85）的大块黄斑视网膜色素上皮（RPE）/脉络膜的RNA测序（RNA-seq）和DNA甲基化微阵列、来自6名AMD和7名对照供体的视网膜、RPE和脉络膜的单核RNA-seq（164,399个细胞）以及单核转座酶可及染色质分析（ATAC）-seq（125,822个细胞）。我们在AMD中鉴定出23个全基因组显著的差异甲基化位点、不同疾病阶段超过1000个差异表达基因以及一种不同于正常或胶质增生的AMD Müller状态。全基因组关联研究（GWAS）位点中的染色质可及性峰值揭示了AMD的潜在因果基因，包括[具体基因1]和[具体基因2]。我们的系统生物学方法揭示了AMD潜在的分子机制，包括WNT信号通路的调节因子[具体调节因子1]和[具体调节因子2]，它们是疾病发生机制中的关键因素。
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