Dataset Information

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).

ABSTRACT: Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1.

SUBMITTER: Kiel C

PROVIDER: S-EPMC7650707 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).

Kiel Christina C Strunz Tobias T International Amd Genomics Consortium Project Manager Susan Blanton Iamdgc Grassmann Felix F Weber Bernhard H F BHF

Cells 20201008 10

Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association ...[more]

PMID: 33050031

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Project description:PurposeAppearance of geographic atrophy (GA) on color photography (CP) is preceded by specific features on spectral-domain optical coherence tomography (SD OCT). We aimed to build SD OCT-based risk assessment models for 5-year new onset of GA and central GA on CP.DesignProspective, longitudinal study.ParticipantsAge-Related Eye Disease Study 2 Ancillary SD OCT study participants with age-related macular degeneration (AMD) with bilateral large drusen or noncentral GA and at least 1 eye without advanced disease (n = 317).MethodsFor 1 eye per participant, qualitative and quantitative SD OCT variables were derived from standardized grading and semiautomated segmentation, respectively, at baseline. Up to 7 years later, annual outcomes were extracted and analyzed to fit multivariate logistic regression models and build a risk calculator.Main outcome measuresNew onset of CP-visible GA and central GA.ResultsOver a follow-up median of 4.0 years and among 292 AMD eyes (without advanced disease at baseline) with complete outcome data, 46 (15.8%) developed central GA. Among 265 eyes without any GA on baseline CP, 70 (26.4%) developed CP-visible GA. Final multivariate models were adjusted for age. In the model for GA, the independent predicting SD OCT factors (P < 0.001-0.03) were: hyperreflective foci and retinal pigment epithelium (RPE) layer atrophy or absence, followed by choroid thickness in absence of subretinal drusenoid deposits, photoreceptor outer segment loss, RPE drusen complex volume, and RPE drusen complex abnormal thinning volume. For central GA, the factors (P < 0.001) were RPE drusen complex abnormal thinning volume, intraretinal fluid or cystoid spaces, hyperreflective foci, and RPE layer atrophy or absence. The models yielded a calculator that computes the probabilities of CP-visible, new-onset GA and central GA after 1 to 5 years.ConclusionsFor AMD eyes with large drusen and no advanced disease, we built a novel risk assessment model-based on age and SD OCT segmentation, drusen characteristics, and retinal pathology-for progression to CP-visible GA over up to 5 years. This calculator may simplify SD OCT grading and with future validation has a promising role as a clinical prognostic tool.

Dataset Information

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).

Publications

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).

Similar Datasets

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