Integrative Genomic Analyses Prioritize CETP -Related Lipid Traits in Age-Related Macular Degeneration

Purpose: To characterize the genetically supported candidate gene landscape of age-related macular degeneration (AMD), identify robust candidate genes, and evaluate the potential roles of cholesteryl ester transfer protein (CETP)-related lipid traits in AMD susceptibility and progression. Methods: Large-scale AMD genome-wide association study discovery and replication cohorts were analyzed using an integrative framework combining single-tissue and cross-tissue transcriptome-wide association studies (TWASs) with MAGMA gene-based analysis. Candidate genes were further evaluated using GTEx expression quantitative trait loci data with summary-data–based Mendelian randomization (SMR) and colocalization analyses. Mendelian randomization (MR), multivariable MR (MVMR), and MR–Bayesian model averaging (MR-BMA) were used to assess CETP-related lipid traits in AMD risk and progression. Results: Integrated evidence from TWASs and MAGMA prioritized seven AMD-associated genes, including CFH, CETP, PLEKHA1, RDH5, HTRA1, AFF1, and ZBTB41. Two-sample MR indicated that genetically predicted CETP-related high-density lipoprotein cholesterol (HDL-C) was associated with increased AMD risk (odds ratio = 1.51; 95% confidence interval, 1.40–1.62; P = 7.0 × 10−27). In MVMR analyses, CETP-related HDL-C retained an independent association, and MR-BMA ranked it as the lipid trait with the highest posterior support. Exploratory analyses suggested that genetically predicted CETP-related HDL-C was associated with AMD progression, including choroidal neovascularization and geographic atrophy. Conclusions: Across discovery and replication cohorts, this multi-cohort, multi-method study prioritized CETP as a genetically supported candidate effector gene for AMD and implicates HDL-C–related genetic variation at the CETP locus in AMD susceptibility and exploratory progression outcomes. These findings support the potential relevance of CETP-related lipid biology but require further mechanistic validation.