Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

Strunz, Tobias; Kiel, Christina; Sauerbeck, Bastian L.; Weber, Bernhard H. F.

doi:10.3390/cells9102267

Cited by 23 publications

(16 citation statements)

References 58 publications

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“…Almost all patients with advanced AMD are over the age of 60 [2]. Genetic factors are also important, and polymorphisms in over 30 genes have been reported to be associated with increased risk of AMD [3]. Others risk factors such as smoking, uncontrolled hypertension, body mass index above 25 have been reported in previous studies [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients

Tsai¹,

Chen²,

Wu³

et al. 2022

Int. J. Med. Sci.

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Purpose:The alteration of the exosomal proteins in the aqueous humor (AH) is linked to the development of eye diseases. The goal of this study was to examine the exosomal protein profile of patients with age-related macular degeneration (AMD) to better understand their role in the pathogenesis of AMD. Methods: Exosomes were isolated from the AH of 28 AMD and 25 control eyes. The quality, concentration, and size distribution of exosomes were measured using a nanoparticle tracking analysis system (NTA). Total exosomal proteins from each sample were purified and digested with trypsin for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Based on LC-MS/MS analysis, we got 105 exosomal peptides from AMD and control patients. Gene ontology (GO) analysis in the biology process revealed that exosomal proteins of AMD were enriched in the lipoprotein metabolic process. T-test analysis revealed six exosomal proteins in patients with AMD were significantly different from controls. Comparing the exosomal protein profile of AMD patients who were receiving anti-VEGF therapy, we observed the amount of two proteins decreased with the duration of the anti-VEGF treatment time. Conclusions: In this study, we successfully isolated and purified AH exosomes. Our results provide pioneering findings for the exosomal protein profile in AMD development and under therapy. These unique proteins could be the new targets for drug discovery or biological markers for evaluating therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients

Tsai¹,

Chen²,

Wu³

et al. 2022

Int. J. Med. Sci.

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“…Therefore, its predictive effect is manifested through integrating its LD connections with the strong SNPs. Moreover, SNP rs7907130 was mapped to a previously identified gene BTBD16 ( Strunz et al, 2020a ) together with the other strong SNPs. It could potentially be a new AMD susceptibility locus.…”

Section: Resultsmentioning

confidence: 99%

Predicting late-stage age-related macular degeneration by integrating marginally weak SNPs in GWA studies

Zhou

Zhang²,

Ding³

et al. 2023

Front. Genet.

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Introduction: Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and the leading cause of blindness in developed countries. Current genome-wide association studies (GWAS) for late-stage age-related macular degeneration are mainly single-marker-based approaches, which investigate one Single-Nucleotide Polymorphism (SNP) at a time and postpone the integration of inter-marker Linkage-disequilibrium (LD) information in the downstream fine mappings. Recent studies showed that directly incorporating inter-marker connection/correlation into variants detection can help discover novel marginally weak single-nucleotide polymorphisms, which are often missed in conventional genome-wide association studies, and can also help improve disease prediction accuracy.Methods: Single-marker analysis is performed first to detect marginally strong single-nucleotide polymorphisms. Then the whole-genome linkage-disequilibrium spectrum is explored and used to search for high-linkage-disequilibrium connected single-nucleotide polymorphism clusters for each strong single-nucleotide polymorphism detected. Marginally weak single-nucleotide polymorphisms are selected via a joint linear discriminant model with the detected single-nucleotide polymorphism clusters. Prediction is made based on the selected strong and weak single-nucleotide polymorphisms.Results: Several previously identified late-stage age-related macular degeneration susceptibility genes, for example, BTBD16, C3, CFH, CFHR3, HTARA1, are confirmed. Novel genes DENND1B, PLK5, ARHGAP45, and BAG6 are discovered as marginally weak signals. Overall prediction accuracy of 76.8% and 73.2% was achieved with and without the inclusion of the identified marginally weak signals, respectively.Conclusion: Marginally weak single-nucleotide polymorphisms, detected from integrating inter-marker linkage-disequilibrium information, may have strong predictive effects on age-related macular degeneration. Detecting and integrating such marginally weak signals can help with a better understanding of the underlying disease-development mechanisms for age-related macular degeneration and more accurate prognostics.

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“…We started with a list of 41 genes based on a list identified as genes with top priority and statistical significance combined in a genome-wide association study (GWAS) published by the International AMD Genomics Consortium (IAMDGC). Currently, this is both the most recent and largest AMD GWAS study and reported 52 independent genetic signals distributed over 34 loci associated with AMD at genome-wide significance [ 38 , 61 ]. There was a significantly different expression profile between LC3b −/− and WT (χ2 = 12.02; two-tailed p value = 0.0005) with 8 DEGs out of 37 mouse orthologs identified (depicted in the heat map, Figure 8 ), including Rdh5 , Slc16a8 , and Htra1 .…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Dhingra

Tobias

Philp

et al. 2023

IJMS

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LC3b (Map1lc3b) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes, such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells, utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis, and neuroprotection. In a mouse model of retinal lipid steatosis-mice lacking LC3b (LC3b−/−), we observed increased lipid deposition, metabolic dysregulation, and enhanced inflammation. Herein, we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b−/− mice revealed 1533 DEGs, with ~73% upregulated and 27% downregulated. Enriched gene ontology (GO) terms included inflammatory response (upregulated DEGs), fatty acid metabolism, and vascular transport (downregulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with a potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.

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Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

Cited by 23 publications

References 58 publications

Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients

Proteomic Profiling of Aqueous Humor Exosomes from Age-related Macular Degeneration Patients

Predicting late-stage age-related macular degeneration by integrating marginally weak SNPs in GWA studies

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

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