scholarly journals Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Madhvi Menon ◽  
Shahin Mohammadi ◽  
Jose Davila-Velderrain ◽  
Brittany A. Goods ◽  
Tanina D. Cadwell ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Single Cell ◽  
Association Studies ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Genome Wide Association Studies ◽  
Human Retina ◽  
Age Related

Abstract Genome-wide association studies (GWAS) have identified genetic variants associated with age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. However, it has been challenging to identify the cell types associated with AMD given the genetic complexity of the disease. Here we perform massively parallel single-cell RNA sequencing (scRNA-seq) of human retinas using two independent platforms, and report the first single-cell transcriptomic atlas of the human retina. Using a multi-resolution network-based analysis, we identify all major retinal cell types, and their corresponding gene expression signatures. Heterogeneity is observed within macroglia, suggesting that human retinal glia are more diverse than previously thought. Finally, GWAS-based enrichment analysis identifies glia, vascular cells, and cone photoreceptors to be associated with the risk of AMD. These data provide a detailed analysis of the human retina, and show how scRNA-seq can provide insight into cell types involved in complex, inflammatory genetic diseases.

scholarly journals New Technologies to Study Functional Genomics of Age-Related Macular Degeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Tu Nguyen ◽  
Daniel Urrutia-Cabrera ◽  
Roxanne Hsiang-Chi Liou ◽  
Chi D. Luu ◽  
Robyn Guymer ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
New Technologies ◽  
Cell Types ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Retinal Cell ◽  
Functional Study ◽  
Age Related

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in people over 50 years old in developed countries. Currently, we still lack a comprehensive understanding of the genetic factors contributing to AMD, which is critical to identify effective therapeutic targets to improve treatment outcomes for AMD patients. Here we discuss the latest technologies that can facilitate the identification and functional study of putative genes in AMD pathology. We review improved genomic methods to identify novel AMD genes, advances in single cell transcriptomics to profile gene expression in specific retinal cell types, and summarize recent development of in vitro models for studying AMD using induced pluripotent stem cells, organoids and biomaterials, as well as new molecular technologies using CRISPR/Cas that could facilitate functional studies of AMD-associated genes.

scholarly journals Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype

2018 ◽  
Author(s):  
Jon M Laurent ◽  
Xin Fu ◽  
Sergei German ◽  
Matthew T Maurano ◽  
Kang Zhang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Cell Types ◽  
Difficult Problem ◽  
Age Related Macular Degeneration ◽  
Functional Sites ◽  
Functional Variants ◽  
Age Related ◽  
Aging Populations

AbstractAge-related Macular Degeneration (AMD) is a leading cause of blindness in the developed world, especially in aging populations, and is therefore an important target for new therapeutic development. Recently, there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci, including a highly significant association at 10q26. The 10q26 risk region contains two genes, HTRA1 and ARMS2, both of which have been separately implicated as causative for the disease, as well as dozens of sites of non-coding variation. To date, no studies have successfully pinpointed which of these variant sites are functional in AMD, nor definitively identified which genes in the region are targets of such regulatory variation. In order to efficiently decipher which sites are functional in AMD phenotypes, we describe a general framework for combinatorial assembly of large ‘synthetic haplotypes’ along with delivery to relevant disease cell types for downstream functional analysis. We demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type ‘assemblon’ covering the HTRA1/ARMS2 risk region. We further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region, delivery and analysis of which will identify functional sites and their effects, leading to an improved understanding of AMD development. We anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.

scholarly journals Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration

2015 ◽  
Author(s):  
Erin K. Wagner ◽  
Yi Yu ◽  
Eric H. Souied ◽  
Sanna Seitsonen ◽  
Ilkka J. Immonen ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Density Lipoprotein ◽  
Age Related Macular Degeneration ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Meta Analyses

ABSTRACTAlthough >20 common frequency age-related macular degeneration (AMD) alleles have been discovered with genome-wide association studies, substantial disease heritability remains unexplained. In this study we sought to identify additional variants, both common and rare, that have an association with advanced AMD. We genotyped 4,332 cases and 25,268 controls of European ancestry from three different populations using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants and performed single variant and gene-based burden tests to identify associations with rare variants. Two protective, low frequency, non-synonymous variants A307V in PELI3 (odds ratio [OR]=0.14, P=4.3×10−10) and N1050Y in CFH (OR=0.76, Pconditional=1.6×10−11) were significantly associated with a decrease in risk of AMD. Additionally, we identified an enrichment of protective alleles in PELI3 using a burden test (OR=0.14). The new variants have a large effect size, similar to rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR=18.82, P=3.5×10−07), C3 K155Q (OR=3.27, P=1.5×10−10), and C9 P167S (OR=2.04, P=2.8×10−07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8x10−07; Firth corrected OR = 0.64, P = 9.6x10−11). This study supports the involvement of both common and low frequency protective variants in AMD. It also may expand the role of the high-density lipoprotein pathway and branches of the innate immune pathway, outside that of the complement system, in the etiology of AMD.

scholarly journals Genetic Mechanism Revealed of Age-Related Macular Degeneration Based on Fusion of Statistics and Machine Learning Method

2021 ◽  
Vol 12 ◽  
Author(s):  
Yongyi Du ◽  
Ning Kong ◽  
Jibin Zhang
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Association Studies ◽  
Area Under The Curve ◽  
Gene Interaction ◽  
Age Related Macular Degeneration ◽  
Support Vector ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Causal Genes

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world which affects the quality of life for millions of elderly individuals worldwide. Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to AMD. To better understand the disease pathogenesis and identify causal genes for AMD, we applied random walk (RW) and support vector machine (SVM) to identify AMD-related genes based on gene interaction relationship and significance of genes. Our model achieved 0.927 of area under the curve (AUC), and 65 novel genes have been identified as AMD-related genes. To verify our results, a statistics method called summary data-based Mendelian randomization (SMR) has been implemented to integrate GWAS data and transcriptome data to verify AMD susceptibility-related genes. We found 45 genes are related to AMD by SMR. Among these genes, 37 genes overlap with those found by SVM-RW. Finally, we revealed the biological process of genetic mutations leading to changes in gene expression leading to AMD. Our results reveal the genetic pathogenic factors and related mechanisms of AMD.

scholarly journals Genetic Basis of Age-related Macular Degeneration

2011 ◽  
Vol 04 (02) ◽  
pp. 119
Author(s):  
Mohammad Othman ◽  
Kari Branham ◽  
John R Heckenlively ◽  
◽  
◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Complex Disease ◽  
Vision Loss ◽  
Association Studies ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Factors Affecting ◽  
Age Related ◽  
Genome Wide

Age-related macular degeneration (AMD) is the main cause of vision loss and impairment in the aging population in developed countries. It is clinically and genetically a complex disease with both environmental and genetic factors affecting the outcome of the disease. Other than the wet type of AMD, there is no treatment for the other forms of AMD. It is estimated that the number of AMD patients will double in the next decade, which will have a significant financial impact on the health system and will compete for health dollars. Understanding the role of genetics in the development of AMD is paramount to help with diagnosis and future treatment. Over the past few years, we have studied the genetics of AMD and reported modest to significant association between AMD and several genes including CFH, ARMS2, TLR4 and ApoE. Our recent genome-wide association studies confirmed these AMD susceptibility loci in addition to other genes in the complement system (C2, C3, CFB and CFI). Recent studies identified new loci near TIMP3 and HDL influencing susceptibility to AMD.

scholarly journals Towards the identification of causal genes for age-related macular degeneration

2019 ◽  
Author(s):  
Fei-Fei Cheng ◽  
You-Yuan Zhuang ◽  
Xin-Ran Wen ◽  
Angli Xue ◽  
Jian Yang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Causal Genes ◽  
Trait Locus ◽  
Eqtl Data

AbstractAge-related macular degeneration (AMD) is a leading cause of visual impairment in ageing populations and has no radical treatment or prevention. Although genome-wide association studies (GWAS) have identified many susceptibility loci for AMD, the underlying causal genes remain elusive. Here, we prioritized nine putative causal genes by integrating expression quantitative trait locus (eQTL) data from blood (n = 2,765) with AMD GWAS data (16,144 cases vs. 17,832 controls) and replicated six of them using retina eQTL data (n = 523). Of the six genes, altering expression of cnn2, sarm1 and bloc1s1 led to ocular phenotype, impaired vision and retinal pigment epithelium (RPE) loss in zebrafish. Essential photoreceptor and RPE genes were downregulated in cnn2- and sarm1-knockdown zebrafishes. Through integration of GWAS and eQTL data followed by functional validation, our study reveals potential roles of CNN2, SARM1 and BLOC1S1 in AMD pathogenesis and demonstrates an efficient platform to prioritise causal genes for human complex diseases.

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