Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration

Han, Xikun; Gharahkhani, Puya; Mitchell, Paul; Liew, Gerald; Hewitt, Alex W.; MacGregor, Stuart

doi:10.1038/s10038-020-0750-x

Cited by 67 publications

(64 citation statements)

References 51 publications

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“…We also investigated how the effect of zinc might directly link with the genes whose polymorphisms have been independently associated with AMD [ 2 , 55 , 56 ]. From these 67 AMD-associated genes, apical zinc supplementation influenced 6, and basal zinc supplementation affected one gene ( Supplementary Figure S3 ).…”

Section: Discussionmentioning

confidence: 99%

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A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

et al. 2020

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In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different human donors. After combining significant differences, we identified the complex molecular networks using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). The cell cultures from the three donors showed extensive pigmentation, development of microvilli and basal infoldings and responded to zinc supplementation with an increase in transepithelial electrical resistance (TEER) (apical supplementation: 443.2 ± 79.3%, basal supplementation: 424.9 ± 116.8%, compared to control: 317.5 ± 98.2%). Significant changes were observed in the expression of 1044 genes, 151 cellular proteins and 124 secreted proteins. Gene set enrichment analysis revealed changes in specific molecular pathways related to cell adhesion/polarity, extracellular matrix organization, protein processing/transport, and oxidative stress response by zinc and identified a key upstream regulator effect similar to that of TGFB1.

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Section: Discussionmentioning

confidence: 99%

“…For overlapping canonical pathway visualization, the network was filtered for 250 significant pathways ( p -value < 0.05) with a minimum of three common shared molecules. A total of 67 entries exported from relevant GWAS studies [ 2 , 55 , 56 ] were used in IPA for overlaying the dataset on AMD-relevant molecules.…”

Section: Methodsmentioning

confidence: 99%

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

et al. 2020

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“…Using a targeted association analysis for miRNA variants, Ghanbari and colleagues (2017) identified an association of AMD with the genetic variant rs2168518, which is located in the seed region of hsa-mir-4513 [ 10 ]. A recent meta-analysis of AMD further supported the association of this variant with AMD [ 11 ].…”

Section: Introductionmentioning

confidence: 97%

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

Kiel

Strunz

Graßmann

et al. 2020

Cells

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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.

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“…To increase the statistical power in order to detect genetic association between SNPs and traits of interest, recent studies have used mtGWAS, which can leverage multiple input summary statistics of the same trait with different measures or different traits with a high genetic correlation [32,38,39]. We combined the use of genotypes imputed to high-density genotype and the mtGWAS approach implemented in MTAG software to increase the statistical power and accuracy of QTL detection [32].…”

Section: Discussionmentioning

confidence: 99%

Multi-trait GWAS using high-density genotypes identifies genes associated with body traits in Nile tilapia

Yoshida¹,

Yáñez²

2020

Preprint

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Background: Body traits are generally controlled by several genes in vertebrates (i.e. polygenes), which in turn make them difficult to identify through association mapping. Increasing the power of association studies by combining approaches such as genotype imputation and multi-trait analysis improves the ability to detect quantitative trait loci associated with polygenic traits, such as body traits. Results: A multi-trait genome-wide association study (mtGWAS) was performed to identify quantitative trait loci (QTL) and genes associated with body traits in Nile tilapia (Oreochromos niloticus) using genotypes imputed to whole-genome sequence (WGS). To increase the statistical power of mtGWAS for the detection of genetic associations, summary statistics from single-trait genome-wide association studies (stGWAS) for eight different body traits recorded in 1,309 animals were used. The mtGWAS increased the statistical power from the original sample size from 13% to 44%, depending on the trait analyzed. The better resolution of the WGS data combined with the increased power of the mtGWAS approach, allowed the detection of significant markers not previously found in the stGWAS. Some lead single nucleotide polymorphisms (SNPs) were found within important functional candidate genes previously associated with growth-related traits. For instance, we identified SNP within the α1,6-fucosyltransferase (FUT8), solute carrier family 4 member 2 (SLC4A2), A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) and heart development protein with EGF like domains 1 (HEG1) genes, which have been associated with average daily gain in sheep, osteopetrosis in cattle, chest size in goats, and growth and meat quality in sheep, respectively. Conclusions: The high-resolution mtGWAS presented, allowed identification of significant SNPs, linked to strong functional candidate genes, associated with body traits in Nile tilapia. These results provide further insights about the genetic variants and genes underlying body trait variation in cichlid fish with high accuracy and strong statistical support.

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Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration

Cited by 67 publications

References 51 publications

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium

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

Multi-trait GWAS using high-density genotypes identifies genes associated with body traits in Nile tilapia

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