scholarly journals CDKN2B-AS1 gene polymorphism is associated with primary open-angle glaucoma in women of the Central Black Earth Region, Russia

2021 ◽  
Author(s):  
NV Eliseeva ◽  
IV Ponomarenko ◽  
MI Churnosov
Keyword(s):  
Gene Polymorphism ◽  
Protective Factor ◽  
Haplotype Block ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Open Angle ◽  
Genome Wide

Primary open-angle glaucoma (POAG) is a complex disorder. Genetic factors play a vital part in POAG. The prevalence of POAG is gender-specific: the disorder is more often diagnosed in women. Results of the genome-wide association studies (GWAS) strongly support the association of CDKN2B-AS1 gene polymorphism with POAG. The aim was to perform the replicative study of CDKN2B-AS1 gene polymorphic loci association with POAG in women of the Central Black Earth Region, Russia. Five CDKN2B-AS1 gene single nucleotide polymorphisms (SNP), rs1063192, rs7865618, rs2157719, rs944800, and rs4977756, were genotyped in 290 female patients with POAG and 220 female controls. The differences in the haplotype block structure between the POAG patients (no haplotype blocks) and the controls (haplotype block consisting of three SNPs, rs1063192, rs7865618 and rs2157719, was detected) for the set of studied CDKN2B-AS1 SNPs were revealed using the Solid Spine algorithm (D’ > 0.8). CDKN2B-AS1 gene haplotype GGG rs1063192–rs7865618–rs2157719 is associated with POAG in women. This haplotype is considered a protective factor of the disorder (OR = 0.66; p = 0.006, рperm = 0.037).

scholarly journals A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer’s disease

2020 ◽  
Author(s):  
Puya Gharahkhani ◽  
Eric Jorgenson ◽  
Pirro Hysi ◽  
Anthony P. Khawaja ◽  
Sarah Pendergrass ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Open Angle ◽  
Risk Genes ◽  
Genome Wide

AbstractWe conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

scholarly journals Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Puya Gharahkhani ◽  
◽  
Eric Jorgenson ◽  
Pirro Hysi ◽  
Anthony P. Khawaja ◽  
...  
Keyword(s):  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Open Angle ◽  
Risk Genes ◽  
Genome Wide ◽  
Causal Variants ◽  
Functional Relevance

AbstractPrimary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

scholarly journals Genetic Predictors of Vascular Regulation of Glaucoma Optic Neuropathy Progression in Patients With Primary Open-Angle Glaucoma

2021 ◽  
pp. 43-50
Author(s):  
Valerii N. Serdiuk ◽  
Oleksii A. Isaiev ◽  
Svitlana B. Ustymenko ◽  
Anton V. Serdiuk
Keyword(s):  
Endothelial Dysfunction ◽  
Gene Polymorphism ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Monogenic Disease ◽  
Open Angle ◽  
Scientific Interest ◽  
Vascular Regulation ◽  
Nos3 Gene

Glaucoma is regarded as a heterogeneous group of diseases with a specific change in biomechanics of the anterior and posterior chambers of the eye, resulting in the increased production and decreased outflow of the aqueous humor. Progressive degeneration of retinal ganglion cells, microglia, astrocytes, Mueller cells leads to chronic damage, thinning of the neuroretinal layer and narrowing of visual field. In this study we investigated primary open-angle glaucoma (POAG). According to many American Optometric Association studies, POAG is the most common type of glaucoma (accounting for up to 72–96 % of cases) characterized by asymptomatic course with gradual decrease in peripheral vision. The reason for this abnormal condition is the optic nerve damage, inefficiency of eye drainage system with fluid accumulation and increased intraocular pressure. Investigation of POAG occurrence and progression becomes more and more relevant each year. Epidemiological studies for the past 50 years showed progressive increase in the incidence of glaucoma. In 5 % of cases, glaucoma is a monogenic disease with Mendelian inheritance. A significant proportion of cases POAG are genetically determined and have a clear hereditary predisposition, which according to various estimates determines from 20 to 60 %. NOS3 gene polymorphism is of considerable scientific interest due to its influence on the development of endothelial dysfunction. Of great scientific interest is determination of the relationship between the rs1799983 and rs2070744 polymorphisms with the development and progression of POAG. Literature review was performed in following database of scientific literature: Web of Science, Google Scholar, PubMed, Scopus etc. Keywords: prevalence of glaucoma, glaucoma epidemiology, gene polymorphism, NOS3 gene, endothelial dysfunction.

Genetic Determinants of Intraocular Pressure

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zihe Xu ◽  
Pirro Hysi ◽  
Anthony P. Khawaja
Keyword(s):  
Intraocular Pressure ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Characteristic Curve ◽  
Annual Review ◽  
Publication Date ◽  
Genome Wide Association Studies ◽  
Open Angle ◽  
Vision Science

Intraocular pressure (IOP) is the cardinal and only modifiable risk factor for glaucoma, the leading cause of irreparable blindness worldwide. Twin and family studies estimate the heritability of IOP to be 40–70%, and linkage studies for IOP have identified numerous loci. Mutations in MYOC can cause markedly elevated IOP and aggressive glaucoma often requiring surgical intervention. However, the majority of the genetic basis for raised IOP and glaucoma in populations is complex, and recent large genome-wide association studies (GWASs) have identified over 100 common variants that contribute to IOP variation. In combination, these loci are predictive for primary open-angle glaucoma in independent populations, achieving an area under the receiver operating characteristic curve of 76% for high-pressure primary open-angle glaucoma; this suggests the possibility of targeted screening in the future. Additionally, GWAS findings have identified important biological pathways underlying IOP regulation, including lymphangiogenesis and lipid metabolism, providing novel targets for new therapies. Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

2021 ◽  
Author(s):  
Valeria Lo Faro ◽  
Arjun Bhattacharya ◽  
Wei Zhou ◽  
Dan Zhou ◽  
Ying Wang ◽  
...  
Keyword(s):  
Primary Cilia ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Open Angle ◽  
Statistical Validation ◽  
Risk Variants ◽  
Genome Wide

Primary open-angle glaucoma (POAG) is a complex eye disease characterized by progressive loss of optic nerve function that, if untreated, ultimately leads to irreversible blindness. To date, the biological mechanisms causing POAG are still unclear. There is disparity in POAG prevalence, clinical presentations, and outcomes across ancestries. Here, we aim to identify unique genetics that underlies risk to POAG and evaluate the potential connection with vascular mechanisms. We performed POAG meta-analysis across 15 biobanks that are part of the Global Biobank Meta-analysis Initiative, with two previously published multi-ancestry analyses for a total of 1,478,037 individuals from six ancestries (46,325 cases and 1,431,712 controls). A total of 109 genome-wide significantly associated loci (p<5e-8) were identified, 18 of which were novel. Three of these novel loci are ancestry-specific, two African- specific and the third specific to northern Europeans. We also identified five sex-specific novel loci, four of which are African-specific and one European-specific. To explore biological implications underlying these variant-trait associations, we performed gene enrichment analysis, gene prioritization analysis and transcriptome-wide association studies (TWAS) implicating genes related to vascular-related functions, blood vessels, angiogenesis, and cancer. A fifth of TWAS-prioritized genes with vascular-related and/or cell senescence/proliferation functional roles or have been implicated in vascular or neoplastic diseases are primary ciliary related genes. We further performed extensive statistical validation analysis of genes in the SIX6 and well-known CDKN2B-AS1 loci, previously implicated in POAG, cardiovascular diseases, and cancers across multiple ancestries. We found evidence of significant interaction between SIX6 rs33912345 and causal variants in chr9p21.3, with concomitant effect on expression of a primary cilia gene CDKN2A and CDKN2B at the CDKN2B-AS1 locus. Phenome-wide association analysis of POAG genetic risk burden across five biobanks and genetic correlation analysis also show the shared biology between POAG and vascular and neoplastic traits. In summary, our findings suggest that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our findings further support the contribution of vascular and proliferation genes in POAG and suggest potential involvement of primary cilia in POAG pathogenesis.

scholarly journals Pharmacogenomics of Lithium Response in Bipolar Disorder

2021 ◽  
Vol 14 (4) ◽  
pp. 287
Author(s):  
Courtney M. Vecera ◽  
Gabriel R. Fries ◽  
Lokesh R. Shahani ◽  
Jair C. Soares ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Association Studies ◽  
Mood Stabilizer ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Lithium Response ◽  
Genetic Loading ◽  
Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

scholarly journals Transcriptional Regulation of RUNX1: An Informatics Analysis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1175
Author(s):  
Amarni L. Thomas ◽  
Judith Marsman ◽  
Jisha Antony ◽  
William Schierding ◽  
Justin M. O’Sullivan ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Runx1 Gene ◽  
Gene Regulatory Elements ◽  
Important Regulator ◽  
Aml1 Gene ◽  
Regulatory Landscape

The RUNX1/AML1 gene encodes a developmental transcription factor that is an important regulator of haematopoiesis in vertebrates. Genetic disruptions to the RUNX1 gene are frequently associated with acute myeloid leukaemia. Gene regulatory elements (REs), such as enhancers located in non-coding DNA, are likely to be important for Runx1 transcription. Non-coding elements that modulate Runx1 expression have been investigated over several decades, but how and when these REs function remains poorly understood. Here we used bioinformatic methods and functional data to characterise the regulatory landscape of vertebrate Runx1. We identified REs that are conserved between human and mouse, many of which produce enhancer RNAs in diverse tissues. Genome-wide association studies detected single nucleotide polymorphisms in REs, some of which correlate with gene expression quantitative trait loci in tissues in which the RE is active. Our analyses also suggest that REs can be variant in haematological malignancies. In summary, our analysis identifies features of the RUNX1 regulatory landscape that are likely to be important for the regulation of this gene in normal and malignant haematopoiesis.

scholarly journals Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders

2021 ◽  
Author(s):  
Robin N Beaumont ◽  
Isabelle K Mayne ◽  
Rachel M Freathy ◽  
Caroline F Wright
Keyword(s):  
Birth Weight ◽  
Statistical Power ◽  
Developmental Disorders ◽  
Association Studies ◽  
Later Life ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Causal Genes

Abstract Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.

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