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 Family-based exome sequencing identifies rare coding variants in age-related macular degeneration

2020 ◽  
Vol 29 (12) ◽  
pp. 2022-2034 ◽  
Author(s):  
Rinki Ratnapriya ◽  
İlhan E Acar ◽  
Maartje J Geerlings ◽  
Kari Branham ◽  
Alan Kwong ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Exome Sequencing ◽  
Target Genes ◽  
Rare Variants ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Genome Wide ◽  
Candidate Target ◽  
Coding Variants

Abstract Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.

scholarly journals Systemic complement levels in patients with age-related macular degeneration carrying rare or low frequency variants in the CFH gene

2021 ◽  
Author(s):  
Sarah de Jong ◽  
Anita de Breuk ◽  
Elena B Volokhina ◽  
Bjorn Bakker ◽  
Alejandro Garanto ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Vision Loss ◽  
Rare Variants ◽  
Low Frequency ◽  
Missense Variant ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Western World ◽  
Complement Factor ◽  
Age Related

Abstract Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world. Genetic variants in the complement factor H (CFH) gene are associated with AMD, but the functional consequences of many of these variants are currently unknown. In this study we aimed to determine the effect of 64 rare and low frequency variants in the CFH gene on systemic levels of factor H (FH) and complement activation marker C3bBbP using plasma samples of 252 carriers and 159 non-carriers. Individuals carrying a heterozygous nonsense, frameshift or missense variant in CFH presented with significantly decreased FH levels, and significantly increased C3bBbP levels in plasma compared to non-carrier controls. FH and C3bBbP plasma levels were relatively stable over time in samples collected during follow-up visits. Decreased FH and increased C3bBbP concentrations were observed in carriers compared to non-carriers of CFH variants among different AMD stages, with the exception of C3bBbP levels in advanced AMD stages, which were equally high in carriers and non-carriers. In AMD families, FH levels were decreased in carriers compared to non-carriers, but C3bBbP levels did not differ. Rare variants in the CFH gene can lead to reduced FH levels or reduced FH function as measured by increased C3bBbP levels. The effects of individual variants in the CFH gene reported in this study will improve the interpretation of rare and low frequency variants observed in AMD patients in clinical practice.

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 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 Casual Effect of Serum Lipid Biomarkers On Early Age-Related Macular Degeneration Using Mendelian Randomization

2021 ◽  
Author(s):  
Fen-Fen Li ◽  
Yuqin Wang ◽  
Qi Chen ◽  
Lue Xiang ◽  
Feng-Qin Rao ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Lipid Biomarkers ◽  
Age Related Macular Degeneration ◽  
Lipoprotein Cholesterol ◽  
European Ancestry ◽  
Age Related ◽  
Increased Risk

Abstract Background Age-related macular degeneration (AMD) is one of the major causes of vision loss. Early AMD needs to be taken seriously, whereas lipid biomarkers’ casual effects on early AMD remain unclear. Methods In this study, a two-sample Mendelian randomization (MR) analysis was performed to systematically assess the causal relationships between seven serum lipid biomarkers, consisting of apolipoprotein A (ApoA), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], and triglycerides (TG), and the risk of early AMD. Totally, 14,034 cases and 91,214 controls of European ancestry were included in the analysis (Number of SNPs = 11,304,110). Results MR estimates showed that a higher HDL-C level was strongly associated with increased risk of early AMD (OR = 1.25, 95% CI: 1.15-1.35, P = 2.61 × 10−8). In addition, the level of ApoA was also positively associated with the risk of early AMD (OR = 2.04, 95% CI: 1.50-2.77, P = 6.27 × 10−6). Conversely, higher LDL-C levels significantly decreased the risk of early AMD (OR = 0.90, 95% CI: 0.85-0.96, P = 2.03 × 10−3). In addition to LDL-C, higher levels of ApoB and TG were found to be positively associated with early AMD risk. Sensitivity analyses further supported these associations. Moreover, multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. Conclusion This study addresses the question of causality relationships that elevated circulating HDL-C/ApoA levels and increased risk of early AMD, whereas LDL-C, ApoB, and TG specifically reduce the risk of early AMD. These findings contribute to our better understanding of the role of lipid metabolism in drusen formation, particularly in early AMD development.

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