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 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 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 Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

2018 ◽  
Author(s):  
David M. Howard ◽  
Mark J. Adams ◽  
Toni-Kim Clarke ◽  
Jonathan D. Hafferty ◽  
Jude Gibson ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Drug Repositioning ◽  
Association Studies ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Brain Regions ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Synaptic Structure ◽  
Genome Wide

AbstractMajor depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.

scholarly journals Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma

2018 ◽  
Vol 27 (8) ◽  
pp. 1486-1496 ◽  
Author(s):  
Yukihiro Shiga ◽  
Masato Akiyama ◽  
Koji M Nishiguchi ◽  
Kota Sato ◽  
Nobuhiro Shimozawa ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Genome Wide Association ◽  
Open Angle ◽  
Susceptibility Loci ◽  
Genome Wide

scholarly journals Association of Common Variants in eNOS Gene with Primary Open Angle Glaucoma: A Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yang Xiang ◽  
Yi Dong ◽  
Xuan Li ◽  
Xin Tang
Keyword(s):  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Meta Analysis ◽  
Fixed Effect Model ◽  
Female Group ◽  
Enos Gene ◽  
Open Angle ◽  
Oxide Synthase ◽  
Stratified Analysis ◽  
Endothelial Nitric Oxide

Purpose. To clarify the association of endothelial nitric oxide synthase (eNOS) polymorphisms and primary open angle glaucoma (POAG).Methods. After a systematic literature search in the MEDLINE, EMBASE, and ISI Web of Science databases, all relevant studies evaluating the association between the polymorphisms (rs2070744 and rs1799983) of eNOS gene and POAG were screened and included. The pooled odds ratios (ORs) and the 95% confidence interval (CI) of each single-nucleotide polymorphism (SNP) in five genetic models were estimated using fixed-effect model ifI2<50%in the test for heterogeneity; otherwise the random-effects model was used.Results. Thirty-one records were obtained, with five being suitable for meta-analysis. The overall results showed that both TT genotype in rs2070744 and GG genotype in rs1799983 are associated with decreased risk of POAG susceptibility. Stratified analysis based on ethnicity showed that the association of rs2070744 with POAG remained only in Caucasians. Results of subgroup analysis by sex indicated association between both polymorphisms and POAG in female group, but not in male group.Conclusions. TT genotype and/or T-allele in rs2070744, as well as GG genotype and/or G-allele in rs1799983, was associated with decreased risk for POAG overall and in female group.

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