Guina Liu ¹ Mingqi Tan ^2,3 Rui Liu ¹ Xuejin Lu ¹ Xiaoshuang Jiang ¹ Yunpeng Bai ³ Zhigang Guo ³ Fang Lu ^1*

• ¹ Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
• ² Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China
• ³ Department of Cardiovascular Surgery, Tianjin Chest Hospital, Tianjin, Tianjin Municipality, China

Age-related macular degeneration (AMD) is a chronic and progressive macular degenerative disease that culminates in a gradual deterioration of central vision loss. Despite its prevalence, the key biomarkers for AMD have not yet been fully elucidated. In this study, we aimed to efficiently identify biomarkers crucial for diagnosing AMD.Three datasets pertaining to retinal pigment epithelium (RPE)/choroid tissues associated with AMD were selected from the GEO database. The GSE50195 dataset was utilized to conduct weighted gene co-expression network analysis (WGCNA) for identifying module genes linked to AMD. KEGG and GO enrichment analyses were subsequently conducted on these module genes. The GSE29801 and GSE135092 datasets were subjected to differential expression analysis to pinpoint the DEGs intersecting with the module genes. Subsequently, wet AMD (wAMD) and dry AMD (dAMD) mouse models were developed, from which RPE/choroid tissues were harvested to validate the hub genes via RT-qPCR and western blot.Using WGCNA, we selected the "antiquewhite4" module (r = 0.91, P = 7e-07), which contains a total of 325 genes. Through the intersection of module genes with DEGs, 9 hub genes were identified. Pathways involved in complement and coagulation cascades, ECM receptor interactions, unsaturated fatty acid biosynthesis and fatty acid elongation play important roles in AMD. Notably, CDH18 demonstrated notable variance across all three datasets. Post validation using RT-qPCR experiments revealed a significant downregulation of CDH18 in both dAMD and wAMD. EGLN3 was expressed at low levels in wAMD. In dAMD, EYA2, LTB, and PODXL were significantly downregulated, while APOC1 was notably upregulated. Western blot confirmed that CDH18 was lowly expressed in dAMD and wAMD mouse models.CDH18 was identified as the key gene involved in the pathogenesis of AMD. An imbalance of the complement and coagulation cascades is a potential mechanism of AMD. This study provides a novel idea for diagnosing and treating AMD in the future.