scholarly journals Prioritization of Cancer-Related Genomic Variants by SNP Association Network

2015 ◽  
Vol 14s2 ◽  
pp. CIN.S17288
Author(s):  
Changning Liu ◽  
Zhenyu Xuan
Keyword(s):  
Association Studies ◽  
Age Related Macular Degeneration ◽  
Chromatin Interaction ◽  
Reference Database ◽  
Genome Wide Association Studies ◽  
Association Network ◽  
Nucleotide Polymorphisms ◽  
Gwas Study ◽  
Snp Association ◽  
Age Related

We have developed a general framework to construct an association network of single nucleotide polymorphisms (SNPs) (SNP association network, SAN) based on the functional interactions of genes located in the flanking regions of SNPs. SAN, which was constructed based on protein-protein interactions in the Human Protein Reference Database (HPRD), showed significantly enriched signals in both linkage disequilibrium (LD) and long-range chromatin interaction (Hi-C). We used this network to further develop two methods for predicting and prioritizing disease-associated genes from genome-wide association studies (GWASs). We found that random walk with restart (RWR) using SAN (RWR-SAN) can greatly improve the prediction of lung-cancer-associated genes by comparing RWR with the use of network in HPRD (AUC 0.81 vs 0.66). In a reanalysis of the GWAS dataset of age-related macular degeneration (AMD), SAN could identify more potential AMD-associated genes that were previously ranked lower in the GWAS study. The interactions in SAN could facilitate the study of complex diseases.

scholarly journals RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) Gene Variants with Predisposition to Age-Related Macular Degeneration

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Alvita Vilkeviciute ◽  
Loresa Kriauciuniene ◽  
Romanas Chaleckis ◽  
Vytenis Pranas Deltuva ◽  
Rasa Liutkeviciene
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Strong Association ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Exudative Amd ◽  
Age Related ◽  
Significant Difference ◽  
The Impact

Background. Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of a central part of the neural retina (macula) and a leading cause of blindness in elderly people. While it is known that the AMD is a multifactorial disease, genetic factors involved in lipid metabolism, inflammation, and neovascularization are currently being widely studied in genome-wide association studies (GWAS). The aim of our study was to evaluate the impact of new single nucleotide polymorphisms (SNPs) in RAD51B, TRIB1, COL8A1, and COL10A1 genes on AMD development. Methods. Case-control study involved 254 patients diagnosed with early AMD, 244 patients with exudative AMD, and 942 control subjects. The genotyping of RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) was carried out using TaqMan assays by a real-time polymerase chain reaction (RT-PCR) method. Results. Statistically significant difference was found in genotype (TT, TC, and CC) distribution of COL8A1 rs13095226 between exudative AMD and control groups (60.2%, 33.6%, and 6.1% vs. 64.9%, 32.3%, and 2.9%, respectively, p=0.036). Also, comparing with TT+TC, rs13095226 CC genotype was associated with 3.5-fold increased odds of exudative AMD development (OR = 3.540; 95% CI: 1.415-8.856; p=0.007). Conclusion. Our study revealed a strong association between a variant in COL8A1 (rs13095226) and exudative AMD development.

scholarly journals Causal associations between risk factors and common diseases inferred from GWAS summary data

2017 ◽  
Author(s):  
Zhihong Zhu ◽  
Zhili Zheng ◽  
Futao Zhang ◽  
Yang Wu ◽  
Maciej Trzaskowski ◽  
...  
Keyword(s):  
Risk Factors ◽  
Protective Effect ◽  
Association Studies ◽  
Significant Risk ◽  
Hdl Cholesterol ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Common Diseases ◽  
Age Related ◽  
Summary Data

AbstractHealth risk factors such as body mass index (BMI), serum cholesterol and blood pressure are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. Genetic methods are useful to infer causality because genetic variants are present from birth and therefore unlikely to be confounded with environmental factors. We develop and apply a method (GSMR) that performs a multi-SNP Mendelian Randomization analysis using summary-level data from large genome-wide association studies (sample sizes of up to 405,072) to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height and years of schooling (EduYears) with a range of common diseases. We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer’s disease, and bidirectional associations with opposite effects (e.g. higher BMI increases the risk of T2D but the effect T2D of BMI is negative). HDL-cholesterol has a significant risk effect on age-related macular degeneration, and the effect size remains significant accounting for the other risk factors. Our study develops powerful tools to integrate summary data from large studies to infer causality, and provides important candidates to be prioritized for further studies in medical research and for drug discovery.

scholarly journals Genotyping-by-Sequencing-Based Genome-Wide Association Studies of Fusarium Wilt Resistance in Radishes (Raphanus sativus L.)

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 858
Author(s):  
O New Lee ◽  
Hyunjin Koo ◽  
Jae Woong Yu ◽  
Han Yong Park
Keyword(s):  
Fusarium Wilt ◽  
Association Studies ◽  
Genotyping By Sequencing ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Gwas Study ◽  
F2 Population ◽  
Genome Wide ◽  
Resistant Varieties

Fusarium wilt (FW) is a fungal disease that causes severe yield losses in radish production. The most effective method to control the FW is the development and use of resistant varieties in cultivation. The identification of marker loci linked to FW resistance are expected to facilitate the breeding of disease-resistant radishes. In the present study, we applied an integrated framework of genome-wide association studies (GWAS) using genotyping-by-sequencing (GBS) to identify FW resistance loci among a panel of 225 radish accessions, including 58 elite breeding lines. Phenotyping was conducted by manual inoculation of seedlings with the FW pathogen, and scoring for the disease index was conducted three weeks after inoculation during two constitutive years. The GWAS analysis identified 44 single nucleotide polymorphisms (SNPs) and twenty putative candidate genes that were significantly associated with FW resistance. In addition, a total of four QTLs were identified from F2 population derived from a FW resistant line and a susceptible line, one of which was co-located with the SNPs on chromosome 7, detected in GWAS study. These markers will be valuable for molecular breeding programs and marker-assisted selection to develop FW resistant varieties of R. sativus.

scholarly journals From the Genetics of Ankylosing Spondylitis to New Biology and Drug Target Discovery

2021 ◽  
Vol 12 ◽  
Author(s):  
Zaarour Nancy ◽  
Li Yan ◽  
Shi Hui ◽  
Bowness Paul ◽  
Chen Liye
Keyword(s):  
Ankylosing Spondylitis ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Drug Target Discovery ◽  
Gwas Study ◽  
Translational Study ◽  
Disease Biology ◽  
Genome Wide ◽  
Causal Genes

Genome-wide association studies (GWAS) have identified 113 single nucleotide polymorphisms (SNPs) affecting the risk of developing ankylosing spondylitis (AS), and an on-going GWAS study will likely identify 100+ new risk loci. The translation of genetic findings to novel disease biology and treatments has been difficult due to the following challenges: (1) difficulties in determining the causal genes regulated by disease-associated SNPs, (2) difficulties in determining the relevant cell-type(s) that causal genes exhibit their function(s), (3) difficulties in determining appropriate cellular contexts to interrogate the functional role of causal genes in disease biology. This review will discuss recent progress and unanswered questions with a focus on these challenges. Additionally, we will review the investigation of biology and the development of drugs related to the IL-23/IL-17 pathway, which has been partially driven by the AS genetics, and discuss what can be learned from these studies for the future functional and translational study of AS-associated genes.

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 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.

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