Genetically predicted CETP-related HDL-C increases age-related macular degeneration risk in a multi-cohort Mendelian randomisation study (Invest Ophthalmol Vis Sci 2026)

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

Invest Ophthalmol Vis Sci · 1 October 2026 · 4

Xu C, Yan Q, Feng C, Li Y, Li X, Zhang R, He J, Wu J

This multi-cohort Mendelian randomisation study combined transcriptome-wide association analyses, MAGMA, SMR, and colocalisation to evaluate CETP-related lipid traits in age-related macular degeneration. Genetically predicted CETP-related high-density lipoprotein cholesterol was associated with increased disease risk (odds ratio = 1.51; 95% confidence interval, 1.40-1.62; P = 7.0 × 10-27). Multivariable MR confirmed an independent association, and MR-Bayesian model averaging ranked it as the lipid trait with the highest posterior support. The analysis also linked CETP-related HDL-C to progression outcomes including choroidal neovascularisation and geographic atrophy. These genetically supported findings implicate CETP locus variation in AMD susceptibility pending further mechanistic validation.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 26 October 2026. Methods.