Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers.
Ontology highlight
ABSTRACT:
SUBMITTER: Sidore C
PROVIDER: S-EPMC4627508 | biostudies-literature | 2015 Nov
REPOSITORIES: biostudies-literature
Publications
Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers.
Sidore Carlo C Busonero Fabio F Maschio Andrea A Porcu Eleonora E Naitza Silvia S Zoledziewska Magdalena M Mulas Antonella A Pistis Giorgio G Steri Maristella M Danjou Fabrice F Kwong Alan A Ortega Del Vecchyo Vicente Diego VD Chiang Charleston W K CWK Bragg-Gresham Jennifer J Pitzalis Maristella M Nagaraja Ramaiah R Tarrier Brendan B Brennan Christine C Uzzau Sergio S Fuchsberger Christian C Atzeni Rossano R Reinier Frederic F Berutti Riccardo R Huang Jie J Timpson Nicholas J NJ Toniolo Daniela D Gasparini Paolo P Malerba Giovanni G Dedoussis George G Zeggini Eleftheria E Soranzo Nicole N Jones Chris C Lyons Robert R Angius Andrea A Kang Hyun M HM Novembre John J Sanna Serena S Schlessinger David D Cucca Francesco F Abecasis Gonçalo R GR
Nature genetics 20150914 11
We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels ...[more]
Similar Datasets
Project description:To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p < 5x10 - 8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR < 0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.
| S-EPMC9164515 | biostudies-literature
Project description:To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p <5×10 -8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p <1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR <0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.
| S-EPMC9094109 | biostudies-literature
Project description:Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value?<?0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p?=?1.8?×?10-11) and TSC22D3 (p?=?1.9?×?10-9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.
| S-EPMC5700078 | biostudies-literature
Project description:BackgroundIn mammals, transitioning from sole milk uptake to the intake of solid feed results in dramatic developmental changes in intestinal function and immunological status. In fact, weaning stress is often accompanied by intestinal inflammatory processes. To develop effective intervention strategies, it is necessary to characterize the developmental pattern and immune response that occurs on weaning, as we have done in this study for piglets.ResultsTo comprehensively delineate cell heterogeneity in ileum tissues and the underlying mechanisms in weaning-induced intestinal inflammation of piglets, we have analyzed the transcriptomes of 42,149 cells from ileum mucosa of normally suckling and post-weaned piglets. There were 31 cell subtypes including epithelial, stromal, and immune cells. A bifurcating trajectory was inferred to separate secretory and absorptive lineages. Integrated cross-species datasets showed well-conserved cellular architectures and transcription signatures between human and pig. Comparative analyses of cellular components, cell-cell communications, and molecular states revealed that T cell subpopulations were significantly altered in weaned piglets. We found that T helper (Th) 17 functional plasticity across changes in the cytokine milieu and the enrichment of granzyme B (GZMB)-expressing cytotoxic T cells potentially exacerbate mucosal inflammation via mitochondrial dysfunction in epithelial cells.ConclusionsOur work has elucidated the single-cell molecular characteristics of the piglet ileum before and after weaning. We have provided an atlas that portrays the landscape of the intestinal pathophysiological inflammatory process associated with weaning, finding a level of conservation between human and pig that support the use of piglets as a model for human infants.
| S-EPMC9153155 | biostudies-literature
Project description:Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.
| S-EPMC7145272 | biostudies-literature
Project description:BackgroundPerhaps reflecting that children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic, little attention has been paid to explore the immune response in pediatric COVID-19. Here, we analyzed the phenotype and function of circulating neutrophils from children with COVID-19.MethodsAn observational study including 182 children with COVID-19, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy children was performed in Buenos Aires, Argentina. Neutrophil phenotype was analyzed by flow cytometry in blood samples. Cytokine production, plasma levels of IgG antibodies directed to the spike protein of SARS-CoV-2 and citrullinated histone H3 were measured by ELISA. Cell-free DNA was quantified by fluorometry.FindingsCompared with healthy controls, neutrophils from children with COVID-19 showed a lower expression of CD11b, CD66b, and L-selectin but a higher expression of the activation markers HLA-DR, CD64 and PECAM-1 and the inhibitory receptors LAIR-1 and PD-L1. No differences in the production of cytokines and NETs were observed. Interestingly, the expression of CD64 in neutrophils and the serum concentration of IgG antibodies directed to the spike protein of SARS-CoV-2 distinguished asymptomatic from mild and moderate COVID-19.InterpretationAcute lung injury is a prominent feature of severe COVID-19 in adults. A low expression of adhesion molecules together with a high expression of inhibitory receptors in neutrophils from children with COVID-19 might prevent tissue infiltration by neutrophils preserving lung function.FundingThis study was supported by the Ministry of Science and Technology (National Agency for Scientific and Technological Promotion, IP-COVID-19-0277 and PMO BID PICT 2018-2548), and University of Buenos Aires from Argentina (20020170100573BA).
| S-EPMC8153212 | biostudies-literature
Project description:In genetic association testing, failure to properly control for population structure can lead to severely inflated type 1 error and power loss. Meanwhile, adjustment for relevant covariates is often desirable and sometimes necessary to protect against spurious association and to improve power. Many recent methods to account for population structure and covariates are based on linear mixed models (LMMs), which are primarily designed for quantitative traits. For binary traits, however, LMM is a misspecified model and can lead to deteriorated performance. We propose CARAT, a binary-trait association testing approach based on a mixed-effects quasi-likelihood framework, which exploits the dichotomous nature of the trait and achieves computational efficiency through estimating equations. We show in simulation studies that CARAT consistently outperforms existing methods and maintains high power in a wide range of population structure settings and trait models. Furthermore, CARAT is based on a retrospective approach, which is robust to misspecification of the phenotype model. We apply our approach to a genome-wide analysis of Crohn disease, in which we replicate association with 17 previously identified regions. Moreover, our analysis on 5p13.1, an extensively reported region of association, shows evidence for the presence of multiple independent association signals in the region. This example shows how CARAT can leverage known disease risk factors to shed light on the genetic architecture of complex traits.
| S-EPMC4746383 | biostudies-literature
Project description:IntroductionVWD-affected females often experience menorrhagia. Periodical fluctuations of the sex steroids during the menstrual cycle cause changes both in the coagulation and immune system. The aim of the current study was to assess the changes in selected inflammatory and endothelial markers in women with VWD during two phases of the menstrual cycle (follicular and luteal) and to compare it with corresponding data from healthy controls.Materials and methodsThe study group included 12 VWD-affected females with regular menstrual cycle, with none of them being prescribed hormone treatment. They were not pregnant or breastfeeding. The control group consisted of 102 healthy females, matched for age and BMI.ResultsWithin the VWD group, endostatin was higher during the follicular phase, compared to the luteal phase, although the difference was not significant (p = 0.062). sICAM-1 and IL-6 were higher in VWD-affected females, compared to the controls, sVCAM-1, cathepsin S and sP-selectin were lower (p<0.003 for all cases). The pattern was constant throughout the menstrual cycle.ConclusionsHigher levels of endostatin during early follicular phase could potentially predispose women with VWD to the development of heavy menstrual bleeding, due to antiangiogenic properties and ability to suppress several coagulation factors. Lower p-selectin levels in VWD group, compared to controls, may also contribute to the bleeding tendency. Changes in other proteins, involved in angiogenesis are hypothetically related to the formation of angiodysplasia-common complication of VWF deficiency. The latter statement requires confirmation in larger studies.
| S-EPMC6328189 | biostudies-literature
Project description:ObjectivesLittle is known about blood cholesterol (blood-C) levels under conditions of infection and limited diet. This study examines blood-C and markers of infection and inflammation in the Tsimane of the Bolivian Amazon, indigenous forager farmers living in conditions that model preindustrial European populations by their short life expectancy, high load of infections and inflammation, and limited diets.MethodsWe use multivariate models to determine the relationships between lipid levels and markers of infection and inflammation. Adult Tsimane (N = 418, age 20-84) were characterized for blood lipids, cells, and inflammatory markers in relation to individual loads of parasites and village region.ResultsMost of the Tsimane (60%) carried at least one parasite species, averaging 1.3 species per person. Serum high-density lipoprotein cholesterol (HDL-C), total cholesterol (total-C), and low-density lipoprotein cholesterol (LDL-C) were below the U.S. norms and varied inversely with markers of infection and inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), immunoglobulin (Ig) E and eosinophil count. Although no relationship of parasite load to blood-C was found, there was an association between anemia and parasite prevalence.ConclusionsWe conclude that the highly infected environment of the Tsimane is related to low levels of blood total-C, HDL-C, and LDL-C. This may suggest a potential reason why arterial disease is largely absent in the Tsimane.
| S-EPMC3537506 | biostudies-literature
Project description:BACKGROUND & AIMS:A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors. METHODS:We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies. RESULTS:Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD. CONCLUSIONS:Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.
| S-EPMC5270616 | biostudies-literature