Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196235 | GEO | 2022/03/09
REPOSITORIES: GEO
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Project description:Genome-wide association studies (GWASs) of eye disorders have identified hundreds of genetic variants associated with ocular disease. However, the vast majority of these variants are noncoding, making it challenging to interpret their function. Here we present a joint single-cell atlas of gene expression and chromatin accessibility of the adult human retina with more than 50,000 cells, which we used to analyze single-nucleotide polymorphisms (SNPs) implicated by GWASs of age-related macular degeneration, glaucoma, diabetic retinopathy, myopia, and type 2 macular telangiectasia. We integrate this atlas with a HiChIP enhancer connectome, expression quantitative trait loci (eQTL) data, and base-resolution deep learning models to predict noncoding SNPs with causal roles in eye disease, assess SNP impact on transcription factor binding, and define their known and novel target genes. Our efforts nominate pathogenic SNP-target gene interactions for multiple vision disorders and provide a potentially powerful resource for interpreting noncoding variation in the eye.
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Project description:Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases
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Project description:HIV-1 integration introduces ectopic transcription factor binding sites into host chromatin. We postulate that the integrated provirus serves as an ectopic enhancer that recruits additional transcriptional factors to the integration locus, increases chromatin accessibility, changes 3D chromatin interactions, and enhances both retroviral and host gene expression. We used 4 well-characterized HIV-1-infected cell line clones having unique integration sites and low to high levels of HIV-1 expression. Using single-cell DOGMA-seq, which captured the heterogeneity of HIV-1 expression and host chromatin accessibility, we found that HIV-1 transcription correlated with HIV-1 accessibility and host chromatin accessibility. HIV-1 integration increased local host chromatin accessibility within ~5–30 kb distance. CRISPRa and CRISPRi-mediated HIV-1 promoter activation and inhibition confirmed integration site-dependent HIV-1-driven changes of host chromatin accessibility. HIV-1 did not drive chromatin confirmation changes at the genomic level (by Hi-C) or the enhancer connectome (by H3K27Ac HiChIP). Using 4C-seq to interrogate HIV-1-chromatin interactions, we found that HIV-1 interacted with host chromatin ~100–300 kb from the integration site. By identifying chromatin regions having both increased transcription factor activity (by ATAC-seq) and HIV-1-chromtain interaction (by 4C-seq), we identified enrichment of ETS, RUNT, STAT, and ZNF transcription factor binding that may mediate HIV-1-host chromatin interactions. Our study found that HIV-1 promoter activity increased host chromatin accessibility, increased HIV-1-host chromatin interactions in an integration site dependent manner, within the existing chromatin boundaries without impacting broader host chromatin structure.
2023-05-01 | GSE229928 | GEO
Project description:BackgroundPrevious studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases.MethodsSummary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results.ResultsThe IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 × 10-04, 95% CI: 5.198 × 10-07 - 2.129 × 10-01, p = 0.0151).ConclusionThis study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases.
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Project description:Expression quantitative trait loci (eQTL) analyses were conducted separately on the glomerular and tubular portions of healthy human kidney samples obtained from subjects of European descent.
2018-11-16 | GSE115098 | GEO
Project description:Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most of the risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. We have performed a cis expression quantitative trait locus (eQTL) screen to investigate whether single nucleotide polymorphisms (SNPs) associated with AIDs influence gene expression in thymus. Genotyping was performed using the Immunochip and 353 AID associated SNPs were tested against expression of surrounding genes (+/- 1 Mb) from human thymic tissue (N=42). We identified eight genes where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.57x10-5). Five genes (FCRL3, RNASET2, C2orf74, SIRPG and SYS1) displayed cis eQTL signals also in other tissues, while for two loci (NPIPB8 and LOC388814), the eQTL signal appear to be thymus-specific. Since many AID risk variants from GWAS have been subsequently fine-mapped in recent Immunochip projects, we explored the overlap between these novel AID risk variants and the thymic eQTL regions. Moreover, we examined the functional annotation of the seven expression altering SNPs (eSNPs). Our study reveals autoimmune risk variants that act as eQTLs in thymus. We have highlighted functional variants within these genetic regions that potentially can represent causal autoimmune risk variants. Total RNA from 42 human thymic samples were obtained from children undergoing cardiac surgery.
2016-01-21 | E-GEOD-77052 | biostudies-arrayexpress
Project description:Observational studies have revealed that dental diseases such as periodontitis and dental caries increase the risk of cardiovascular diseases (CVDs). However, the causality between periodontal disease (PD) and CVDs is still not clarified. In the present study, two-sample Mendelian randomization (MR) studies were carried out to assess the association between genetic liability for periodontal diseases (dental caries and periodontitis) and major CVDs, including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and stroke-including ischemic stroke as well as its three main subtypes-based on large-scale genome-wide association studies (GWASs). Our two-sample MR analyses did not provide evidence for dental caries and periodontitis as the causes of cardiovascular diseases; sensitivity analyses, including MR-Egger analysis and weighted median analysis, also supported this result. Gene functional annotation and pathway enrichment analyses indicated the common pathophysiology between cardiovascular diseases and periodontal diseases. The associations from observational studies may be explained by shared risk factors and comorbidities instead of direct consequences. This also suggests that addressing the common risk factors-such as reducing obesity and improving glucose tolerance-could benefit both conditions.
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Project description:Debilitating eye diseases such as age-related macular degeneration and retinitis pigmentosa currently represent a large unmet medical need that could potentially be addressed by stem cell therapy. A number of novel stem cell-based cellular therapies are now under development to treat a variety of eye diseases. The approaches being taken by the California Institute for Regenerative Medicine, together with its grantees, are discussed.
| S-EPMC4250220 | biostudies-literature
Project description:PurposeSystemic inflammation is potentially associated with ocular diseases such as late age-related macular degeneration (AMD). Using the serum concentration of high-sensitive C-reactive protein (hs-CRP) as surrogate of systemic inflammation, we examined potential associations between the serum hs-CRP concentration and the presence and degree of eye diseases.MethodsThe population-based Beijing Eye Study included 3468 Chinese individuals. The study participants underwent a standardized interview and a detailed ophthalmic examination. The serum concentration of hs-CRP was determined.ResultsOut of 3468 participants, 2452 (70.7%) individuals (mean age:63.4±9.4 year; range:50-91 years) had hs-CRP measurements (mean:1.96±4.07mg/L). In multivariate analysis, higher serum concentration of hs-CRP was significantly (regression coefficient r: 0.21) associated with a higher level of diabetic retinopathy (P = 0.007; standardized regression coefficient beta:0.06; non-standardized regression coefficient B:1.35; 95% confidence interval (CI):0.37,2.22) and polypoidal choroidal vasculopathy (P = 0.002;beta:0.06;B:6.22;95%CI:2.24,10.2) after adjusting for higher serum concentration of high-density lipoproteins (P<0.001;beta:-0.12;B:-1.31;95%CI:-1.77,-0.85), higher body mass index (P = 0.01;beta:0.06;B:0.06;95%CI:0.01, 0.11), lower level of education (P = 0.04;beta:-0.06;B:-0.22;95%CI:-0.42,-0.02), lower cognitive function score (P = 0.01;beta:-0.07;B:-0.08;95%CI:-0.13,-0.02). If the presences of other ocular diseases were added to the model, the presence of glaucoma (P = 0.99), open-angle glaucoma (P = 0.80), angle-closure glaucoma (P = 0.67), pseudoexfoliation (P = 0.18), nuclear cataract (P = 0.30), cortical cataract (P = 0.15), subcapsular cataract (P = 0.59), retinal vein occlusions (P = 0.33), central serous choroidopathy (P = 0.44), early stage of age-related macular degeneration (AMD) (P = 0.46), intermediate stage of AMD (P = 0.20) and late stage of AMD (P = 0.91) including geographic atrophy (P = 0.60) or neovascular AMD (P = 0.68) were not significantly associated with the serum concentration of hs-CRP.ConclusionsIn Chinese aged 50+ years, higher serum concentration of hs-CRP was significantly associated with a higher level of diabetic retinopathy and higher frequency of polypoidal choroidal vasculopathy. Other major ocular disorders, namely glaucoma including open-angle glaucoma and angle-closure glaucoma, pseudoexfoliation, nuclear, cortical or subcapsular cataract, retinal vein occlusions, central serous choroidopathy, early, intermediate or late stage of AMD including geographic atrophy, were not significantly associated with hs-CRP serum concentrations. It suggests that these diseases, in contrast to diabetic retinopathy and polypoidal choroidal vasculopathy, were not associated with a major systemic inflammatory component.
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Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7.
2023-08-11 | GSE222373 | GEO