Multimodal Imaging of Nonneovascular Age-Related Macular Degeneration

Garrity, Sean T.; Sarraf, David; Freund, K. Bailey; Sadda, Srinivas R

doi:10.1167/iovs.18-24158

Cited by 64 publications

(60 citation statements)

References 154 publications

(203 reference statements)

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“…Second, we contrasted advanced AMD effect sizes (IAMDGC data (9)) with early AMD effect sizes (our meta-analysis,) for the 34 known advanced AMD lead variants ( Figure 2, Table S13 ). We found two classes of variants: (1) 25 variants showed nominally significant effects on early AMD (P<0.05; “advanced-and-early-AMD loci”), all directionally consistent and all smaller for early vs. advanced AMD (OR early =1.04-1.47; OR adv =1.10-2.81); (2) nine variants had no nominally significant effect on early AMD (P≥0.05; “advanced-only AMD loci”). We did not find any variant with early AMD effects into the opposite direction as the advanced AMD effects.…”

Section: Resultsmentioning

confidence: 82%

“…We found several interesting aspects ( Table 3 ): (1) When prioritizing variants according to their statistical evidence for being the driver variant by computing 95% credible sets of variants (27), we found 23 and 294 credible set variants for the CD46 and TYR locus, respectively ( Table S3 ). (2) Using the Variant Effect Predictor (28), we assessed overlap of credible set variants with functional regulatory regions and found variants influencing the transcript and/or the protein for four genes ( Table S4 ): variants causing an alternative splice form for CD46 , a nonsense-mediated mRNA decay (NMD) for CR1L , a missense variant for TYR (rs1042602, r 2 =0.56 to the lead variant rs621313), and NMD variants for NOX4. (3) We investigated credible set variants for being an expression quantitative trait locus (eQTL) for any of the 17 genes in retina (Eye Genotype Expression database, EyeGEx (29)) or in 44 other tissues (Genotype-Tissue Expression database, GTEx (30)).…”

Section: Resultsmentioning

confidence: 99%

“…This would also suggest that mechanisms of complement system or lipid metabolism trigger both early and advanced disease. (2) For a mechanism that triggers advanced AMD no matter whether the person is “healthy” or has early AMD, we would anticipate a variant effect for advanced AMD, but not for early AMD ( Figure 3 , Model 2). This would be in line with our observed associations for the nine “advanced-AMD-only” loci.…”

Section: Discussionmentioning

confidence: 99%

“…The method assumes a single causal signal per locus. (2) Variant effect predictor (VEP) to explore whether any of the credible variants was located in a relevant regulatory gene region (28). (3) eQTL analysis: We downloaded expression summary statistics for the candidate genes in retina from the EyeGEx database (29) and for 44 other tissues from the GTEx database (30) (both available at www.gtexportal.org/home/datasets) and evaluated whether any of the credible variants showed significant effects on expression levels in the aggregated data.…”

Section: Methodsmentioning

confidence: 99%

“…We compared effect sizes in a scatter plot and clustered the lead variants by their nominal significant association on advanced and/or early AMD. We classify different types of loci in a similar fashion as done previously for adiposity trait genetics (41): (1) “advanced-and-early” AMD loci (P early <0.05, P adv <0.05), (2) “advanced-only” AMD loci (P early ≥0.05, P adv <0.05), (3) “early-only” AMD loci (P early <0.05, P adv ≥0.05).…”

Section: Methodsmentioning

confidence: 99%

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Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

Winkler

Graßmann

Brandl

et al. 2019

Preprint

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33Background: Advanced age-related macular degeneration (AMD) is a leading cause of 34 blindness. While around half of the genetic contribution to advanced AMD has been 35 uncovered, little is known about the genetic architecture of the preceding early stages of the 36 diseases. 37Methods: To identify genetic factors for early AMD, we conducted a genome-wide association 38 meta-analysis with 14,034 early AMD cases and 91,214 controls from 11 sources of data 39 including data from the International AMD Genomics Consortium (IAMDGC) and the UK 40 Biobank (UKBB). We ascertained early AMD via color fundus photographs by manual grading 41 for 10 sources and by using an automated machine learning approach for >170,000 images 42 from UKBB. We searched for significant genetic loci in a genome-wide association screen 43 (P<5x10 -8 ) based on the meta-analysis of the 11 sources and via a candidate approach based 44 on 13 suggestive early AMD variants from Holliday et al 2013 (P<0.05/13, additional 3,432 45 early AMD cases and 11,235 controls). For the novel AMD regions, we conducted in-silico 46 follow-up analysis to prioritize causal genes and pathway analyses. 47 Results:We identified 11 loci for early AMD, 9 novel and 2 known for early AMD. Most of 48 these 11 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, APOE, 49 C2, C3, CETP, PVRL2, TNFRSF10A, VEGFA), except two that were completely novel to any 50 AMD. Among the 17 genes within the two novel loci, in-silico functional annotation suggested 51 CD46 and TYR as the most likely responsible genes. We found the presence or absence of 52 an early AMD effect to distinguish known pathways of advanced AMD genetics 53 (complement/lipid pathways or extracellular matrix metabolism, respectively). 54 Conclusions:Our data on early AMD genetics provides a resource comparable to the existing 55 data on advanced AMD genetics, which enables a joint view. Our large GWAS on early AMD 56 identified novel loci, highlighted shared and distinct genetics between early and advanced 57 AMD and provides insights into AMD etiology. The ability of early AMD effects to differentiate 58 the major pathways for advanced AMD underscores the biological relevance of a joint view on 59 early and advanced AMD genetics. 60 KEYWORDS 61Genome-wide association study (GWAS); Meta-analysis; Age-related macular degeneration 62 (AMD); Early AMD; CD46; TYR; International AMD Genomics Consortium (IAMDGC); UK 63 Biobank (UKBB); machine-learning; automated phenotyping 64 65 BACKGROUND 66Age-related macular degeneration (AMD) is the leading cause of irreversible central vision 67 impairment in industrialized countries. Advanced AMD presents as geographic atrophy (GA) 68 and/or neovascular (NV) complications (1). Typically, advanced AMD is preceded by clinically 69 asymptomatic and thus often unrecognized early disease stages. Early AMD is characterised 70 by differently sized yellowish accumulations of extracellular material between Bruch's 71 membrane and retinal pigment epithelium (RPE) or betwee...

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

Winkler

Graßmann

Brandl

et al. 2019

Preprint

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Association of Metformin With the Development of Age-Related Macular Degeneration

et al. 2023

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ImportanceAge-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.ObjectiveTo investigate the association between metformin use and age-related macular degeneration (AMD).Design, Setting, and ParticipantsThe Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.InterventionsParticipants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.Main Outcomes and MeasuresPrevalence of AMD in the treatment arms.ResultsOf 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).Conclusions and RelevanceThese data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.

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Ocular Imaging for Enhancing the Understanding, Assessment, and Management of Age-Related Macular Degeneration

Nassisi

Sadda

2021

Age-Related Macular Degeneration

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Multimodal Imaging of Nonneovascular Age-Related Macular Degeneration

Cited by 64 publications

References 154 publications

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease

Association of Metformin With the Development of Age-Related Macular Degeneration

Ocular Imaging for Enhancing the Understanding, Assessment, and Management of Age-Related Macular Degeneration

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