VIKING Health Study - Shetland
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ABSTRACT:
PROVIDER: EGAS00001003872 | EGA |
REPOSITORIES: EGA
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Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.
2022-10-14 | PXD031969 | Pride
Project description:In this study, we explored the possibility that rare variation in the genetic background may be an additional risk factor for Parkinson's Disease (PD) in families segregating pathogenic GBA gene variants. We performed whole-genome sequencing, rare variant filtering, segregation analysis and functional validation of PD cosegregating rare genetic variation in two families segregating PD associated GBA variants c.115+1G>A (ClinVar ID: 93445, ) and p.L444P (ClinVar ID: 4288) respectively. We found rare genetic variation in the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families.
| EGAS00001004777 | EGA
Project description:Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and SNP arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g. PARP1, CDKN2A) or co-segregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare co-segregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
2016-12-01 | GSE85010 | GEO
Project description:Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch and UK individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***
2010-02-28 | GSE20332 | GEO
Project description:Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***
2010-02-28 | GSE20142 | GEO
Project description:Obesity is a major risk factor for many common diseases and has a significant heritable component. While clinical and large-scale population studies have identified several genes harbouring rare alleles with large effects on obesity risk, there are likely many unknown genes with highly penetrant effects remaining. To this end, we performed whole exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare, loss of function variants in two genes – BSN and APBA1 – with effects on BMI substantially larger than well-established obesity genes such as MC4R. One in ~6500 individuals carry a heterozygous protein truncating variant (PTV) in BSN, which confers a 6.6, 3.7 and 3-fold higher risk of severe obesity (BMI >40kg/m2), non-alcoholic fatty liver disease and type 2 diabetes, respectively. Rare PTVs in BSN were found in three patients with severe early onset obesity, but in contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN PTVs magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect on BMI twice as large in BSN PTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human iPSC-derived hypothalamic neurons. These approaches highlighted a network of differentially expressed genes that were collectively enriched for genomic regions associated with BMI, and suggest emerging roles for neurodevelopment, neurogenesis, and altered neuronal oxidative phosphorylation in the etiology of obesity.
2024-01-29 | GSE243112 | GEO
Project description:In psychiatric disorders, common and rare genetic variants cause widespread dysfunction of cells and their interactions, especially in the prefrontal cortex, giving rise to psychiatric symptoms. To better understand these processes, we traced the effects of common and rare genetics, and cumulative disease risk scores, to their molecular footprints in human cortical single-cell types. We demonstrated that examining gene expression at single-exon resolution is crucial for understanding the cortical dysregulation associated with diagnosis and genetic risk derived from common variants. We then used disease risk scores to identify a core set of genes that serve as a footprint of common and rare variants in the cortex. Pathways enriched in these genes included dopamine regulation, circadian entrainment, and hormone regulation. Single-nuclei-RNA-sequencing pinpointed these enriched genes to excitatory cortical neurons. This study highlights the importance of studying sub-gene-level genetic architecture to classify psychiatric disorders based on biology rather than symptomatology, to identify novel targets for treatment development.
2022-11-17 | GSE208338 | GEO
Project description:Individuals with Down syndrome (DS) are at an increased risk for developing congenital heart defects especially atrioventricular septal defects (AVSD). Our goal was to identify the contribution of copy number variants (CNV) to DS-associated AVSD. We used the Affymetrix SNP 6.0 genotyping platform to comprehensively characterize CNVs in 452 ethnically matched individuals with DS, comprising of 210 cases (DS + complete AVSD) and 242 controls with a structurally normal heart (DS + NH). Results from burden and region-wise analyses using PLINK revealed that despite the 2000 fold elevated risk, common CNVs of large effect (OR > 2.0) do not account for the increased risk observed in DS-associated AVSD. In contrast, cases do harbor a significantly elevated burden of large rare variants (> 100kb, < 1% frequency) (p < 0.01) and case deletions intersect genes more often than those observed in controls (p < 0.007). Gene enrichment analysis showed a trend for enrichment among deletions impacting the ciliome pathway in cases compared to controls. Our findings suggest that the etiology of AVSD is highly complex and does not arise from the action of a few common variants of large effect. Instead, our data support a multifactorial model, wherein large rare deletions play a significant role in elevating the risk of AVSD in a trisomic background. Copy Number Variation Analysis of individuals with DS using Affymetrix SNP 6.0 genotyping platform. A composite reference was generated using the same dataset to derive the log2 ratios using Affymetrix Power Tols (APT). Submitting here the preliminary data from 437 subjects, 15 were excluded due to privacy concerns.
2014-10-24 | E-GEOD-60607 | biostudies-arrayexpress
Project description:Background: While BMPR2 mutation strongly predisposes to pulmonary arterial hypertension (PAH), only 20% of mutation carriers develop clinical disease. This finding suggests that modifier genes contribute to FPAH clinical expression. Since modifiers are likely to be common alleles, this problem is not tractable by traditional genetic approaches. Further, examination of gene expression is complicated by confounding effects attributable to drugs and the disease process itself. Methods: To resolve these problems, B-cells were isolated, EBV-immortalized, and cultured from familial PAH patients with BMPR2 mutations, mutation positive but disease-free family members, and family members without mutation. This allows examination of differences in gene expression without drug or disease-related effects. These differences were assayed by Affymetrix array, with follow-up by quantitative RT-PCR and additional statistical analyses. Results: By gene array, we found consistent alterations in multiple pathways with known relationship to PAH, including actin organization, immune function, calcium balance, growth, and apoptosis. Selected genes were verified by quantitative RT-PCR using a larger sample set. Analysis of overrepresented gene ontology groups suggests that it is pathway-specific, not gene-specific changes that carry increased risk of disease. Conclusions: B-cell lines are a valuable and accessible tool for assaying alterations in gene expression free from drug and disease effects. Predisposition to disease within BMPR2 mutation carriers was linked to several pathways, including proliferation, GTP signaling, and stress response. Experiment Overall Design: Immortalized B-cells from BMPR2 mutation carriers with and without disease are compared to search for modifier genes
2008-10-25 | E-GEOD-10767 | biostudies-arrayexpress