Author Correction: Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration

Ratnapriya, Rinki; Sosina, Olukayode A.; Starostik, Margaret R.; Kwicklis, Madeline; Kapphahn, Rebecca J.; Fritsche, Lars G.; Walton, Ashley; Arvanitis, Marios; Gieser, Linn; Pietraszkiewicz, Alexandra; Montezuma, Sandra R.; Chew, Emily Y.; Battle, Alexis; Abecasis, Gonçalo R.; Ferrington, Deborah A.; Chatterjee, Nilanjan; Swaroop, Anand

doi:10.1038/s41588-019-0430-y

Cited by 14 publications

(21 citation statements)

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“…The CFH gene was significantly associated in all but the RPE3 and RPE4 subpopulations (Figure 6, Supplementary Data 1). Compared to a previous TWAS analysis based on bulk eQTL datasets 28 , PARP12 gene was also replicated in our single-cell TWAS in the RPE1 cell eQTL data (Figure 6, Supplementary Data 1). For the previously reported gene RLBP1 28 , nearby gene IDH2 was identified instead.…”

Section: Transcriptome-wide Association Study Analysis Identifies Novel Genetic Associations For Geographic Atrophysupporting

confidence: 74%

“…Compared to a previous TWAS analysis based on bulk eQTL datasets 28 , PARP12 gene was also replicated in our single-cell TWAS in the RPE1 cell eQTL data (Figure 6, Supplementary Data 1). For the previously reported gene RLBP1 28 , nearby gene IDH2 was identified instead. Interestingly, the top GWAS SNP rs2238307 in gene IDH2 is highly correlated with the top SNP rs3825991 in PARP12 (r2 = 0.77) (Supplementary Data 1).…”

Section: Transcriptome-wide Association Study Analysis Identifies Novel Genetic Associations For Geographic Atrophysupporting

confidence: 74%

“…Mapping expression quantitative trait loci (eQTL) is a powerful approach to elucidate functional mechanisms of common genetic variants, allowing the allelic effect of a variant on disease risk to be linked to changes in gene expression. Three recent studies applied eQTL mapping in post-mortem retina to investigate the regulation of gene expression and identified eQTL variants regulating gene expression with a subset of these eQTL associated with AMD in GWAS [26][27][28] . Molecular and genetic profiling of RPE in healthy and diseased tissue would likely improve our understanding of the mechanisms that confer disease risk or contribute to geographic atrophy progression.…”

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confidence: 99%

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Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Senabouth

Daniszewski

Lidgerwood

et al. 2021

Preprint

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Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

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Section: Transcriptome-wide Association Study Analysis Identifies Novel Genetic Associations For Geographic Atrophysupporting

confidence: 74%

Section: Transcriptome-wide Association Study Analysis Identifies Novel Genetic Associations For Geographic Atrophysupporting

confidence: 74%

mentioning

confidence: 99%

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Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Senabouth

Daniszewski

Lidgerwood

et al. 2021

Preprint

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“…Advances in sequencing technologies, genetic analyses, such as genome-wide association studies (GWAS), using large numbers of samples from donors with AMD, enables identification of common and rare variation that is associated with AMD 4 . Moreover, expression quantitative trait loci (eQTL) analysis using transcriptional profiles of postmortem retinas from 453 controls and AMD patients expanded the genetic landscape of AMD 5 . Such studies also have implicated roles for the immune system, in particular the dysregulation of the complement system, in the pathogenesis and severity of AMD 6 .…”

Section: Mainmentioning

confidence: 99%

Retinal aging transcriptome and cellular landscape in association with the progression of age-related macular degeneration

Wang

Wong

Liu

2022

Preprint

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Age is the main risk factor for age-related macular degeneration (AMD), a leading cause of blindness in the elderly, with limited therapeutic options. Here we systematically analyzed the transcriptomic characteristics and cellular landscape of the aging retina from controls and patients with AMD. We identify the aging genes in the retina that are associated with innate immune response and inflammation. Deconvolution analysis reveals that the estimated proportion of M2 and M0 macrophages is increased and decreased, respectively with both age and AMD severity. Moreover, we find that Müller glia are increased with age but not with disease severity. Several genes associated with both age and disease severity in AMD, particularly C1s and MR1, are strong positively correlated with the proportions of Müller glia. Our studies expand the genetic and cellular landscape of AMD and provide avenues for further studies on the relationship between age and AMD.

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“…Vallée et al ( 45 ) provided a survey that highlighted the importance of circadian rhythm dysregulation in exudative (wet) AMD by abnormal upregulation of the canonical WNT/β-catenin pathway ( 45 ). Ratnapriya et al ( 46 ) conducted a study on the genetic landscape of AMD and built an Eye Genotype Expression (EyeGEx) database for the post-GWAS-based interpretation of ocular traits ( 46 ). Brooks et al ( 47 ) performed an interesting analysis to determine the regulatory signals deficient in building retinal organoids and yielded the experimental validation through generating a mature retina in vitro , hence facilitating research in the disease modeling and evaluation of therapeutic interventions ( 47 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Epigenetic Clock Biomarkers of Age-Related Macular Degeneration

Mallik¹,

Grodstein²,

Bennett³

et al. 2022

Front. Med.

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Age-Related Macular Degeneration (AMD) is a bilateral ocular condition resulting in irreversible vision impairment caused by the progressive loss of photoreceptors in the macula, a region at the center of the retina. The progressive loss of photoreceptor is a key feature of dry AMD but not always wet AMD, though both forms of AMD can lead to loss of vision. Regression-based biological age clocks are one of the most promising biomarkers of aging but have not yet been used in AMD. Here we conducted analyses to identify regression-based biological age clocks for the retina and explored their use in AMD using transcriptomic data consisting of a total of 453 retina samples including 105 Minnesota Grading System (MGS) level 1 samples, 175 MGS level 2, 112 MGS level 3 and 61 MGS level 4 samples, as well as 167 fibroblast samples. The clocks yielded good separation among AMD samples with increasing severity score viz., MGS1-4, regardless of whether clocks were trained in retina tissue, dermal fibroblasts, or in combined datasets. Clock application to cultured fibroblasts, embryonic stem cells, and induced Pluripotent Stem Cells (iPSCs) were consistent with age reprograming in iPSCs. Moreover, clock application to in vitro neuronal differentiation suggests broader applications. Interesting, many of the age clock genes identified include known targets mechanistically linked to AMD and aging, such as GDF11, C16ORF72, and FBN2. This study provides new observations for retina age clocks and suggests new applications for monitoring in vitro neuronal differentiation. These clocks could provide useful markers for AMD monitoring and possible intervention, as well as potential targets for in vitro screens.

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Author Correction: Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration

Cited by 14 publications

References 0 publications

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Retinal aging transcriptome and cellular landscape in association with the progression of age-related macular degeneration

Novel Epigenetic Clock Biomarkers of Age-Related Macular Degeneration

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