scholarly journals The Polygenic and Monogenic Basis of Blood Traits and Diseases

2020 ◽  
Author(s):  
Dragana Vuckovic ◽  
Erik L. Bao ◽  
Parsa Akbari ◽  
Caleb A. Lareau ◽  
Abdou Mousas ◽  
...  
Keyword(s):  
Blood Cell ◽  
Genetic Variants ◽  
Gene Networks ◽  
Large Scale ◽  
European Ancestry ◽  
Mendelian Genetics ◽  
Physiological Processes ◽  
Clinical Disorders ◽  
Cell Phenotypes ◽  
Significant Health

SummaryBlood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including 563,946 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering the full allele frequency spectrum of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood cell traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell GWAS to interrogate clinically meaningful variants across the full allelic spectrum of human variation.

Full title: A large‐scale transcriptome‐wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine‐mapping

2021 ◽  
Author(s):  
Amanda L. Tapia ◽  
Bryce T. Rowland ◽  
Jonathan D. Rosen ◽  
Michael Preuss ◽  
Kris Young ◽  
...  
Keyword(s):  
Blood Cell ◽  
Association Study ◽  
Fine Mapping ◽  
Large Scale ◽  
Cell Phenotypes

scholarly journals A Mendelian randomization study of telomere length and blood-cell traits

2020 ◽  
Author(s):  
Charleen D. Adams ◽  
Brian B. Boutwell
Keyword(s):  
Blood Cell ◽  
Telomere Length ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Mean Corpuscular Hemoglobin ◽  
Corpuscular Hemoglobin ◽  
Standard Deviation Increase ◽  
Mean Cell Volume ◽  
Distribution Width

AbstractWhether telomere attrition reducing proliferative reserve in blood-cell progenitors is causal has important public-health implications. Mendelian randomization (MR) is an analytic technique using germline genetic variants as instrumental variables. If certain assumptions are met, estimates from MR should be free from most environmental sources of confounding and reverse causation. Here, two-sample MR is performed to test whether longer telomeres cause changes to hematological traits. Summary statistics for genetic variants strongly associated with telomere length were extracted from a genome-wide association (GWA) study for telomere length in individuals of European ancestry (n=9190) and from GWA studies of blood-cell traits, also in those of European ancestry (n∼173,000 participants). A standard deviation increase in genetically influenced telomere length increased red blood cell (RBC) and white blood cell (WBC) counts, decreased mean corpuscular hemoglobin (MCH) and mean cell volume (MCV), and had no observable impact on mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), hematocrit, or hemoglobin. Sensitivity tests for pleiotropic distortion were mostly inconsistent with glaring violations to the MR assumptions. Similar to how germline mutations in TERT can lead to bone-marrow failure, these data provide evidence that genetically influenced common variation in telomere length impacts hematologic traits in the population.

Large Scale Discoveries of Genes and Polymorphisms Associated with Variation in Hematologic Traits

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-40-SCI-40
Author(s):  
Nicole Soranzo
Keyword(s):  
Blood Cell ◽  
Genetic Variants ◽  
Blood Cells ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Conflicts Of Interest ◽  
Cell Types ◽  
The Novel ◽  
Hematopoietic Stem ◽  
Genome Wide

Abstract Hematopoiesis generates mature blood cells from hematopoietic stem cells (HSC) in distinct lineages to release of trillions of mature cells each day into the peripheral blood stream to perform essential functions such as oxygen transport, hemostasis and host defense. The formation and turnover of blood cells are tightly controlled and so the properties of blood cells, including their volume and count, have large heritabilities and are easily influenced by genetic variation. Here we describe the most statistically powerful genome wide association study (GWAS) of blood cell indices to date. We tested associations of 29.5 million polymorphic DNA sequence variants derived using the the Affymetrix axiom array with interpolation of 20 million variants using the UK 10000 genome data with 36 different hematological indices of red cells, white cells and platelets, some of which, such as the reticulocyte count, have been explored for the first time. We discovered significant associations at thousands of associated genetic variants, including hundreds of associations for low frequency genetic variants, thus identifying associations with larger effects on indices than those reported for common variants by previous discovery studies. We have described detailed follow-up studies of the novel associations. Using cell type-specific epigenome and gene expression data generated by the BLUEPRINT project and results from chromatin conformation capture in major blood cell types, we can identify the likely causal variants and their functional impact at a large number of the novel loci. Finally, we have evaluated the contribution of genetic variants to common and complex diseases. In conclusion, we have interrogated phenotypes across the whole hematopoietic tree and increased the number of traits associated with blood cell phenotypes by an order of magnitude. Overall, our results demonstrate widespread and powerful genetic influences on the formation and regulation of the major human blood cell types, identifying many novel genes involved and show the value of genome-wide functional annotation from relevant primary cell populations for interpreting genetic association results. Disclosures No relevant conflicts of interest to declare.

scholarly journals The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study

2019 ◽  
Vol 110 (3) ◽  
pp. 685-690 ◽  
Author(s):  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Linoleic Acid ◽  
Blood Cell ◽  
White Blood Cell ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

ABSTRACT Background Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n–6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials. Objectives To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma. Methods We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)–control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality. Results Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (−0.03; 95% CI: −0.061, −0.004) and lower neutrophil count (−0.04; 95% CI: −0.057, −0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses. Conclusions LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

Development and study of a method for cell separation during white blood cell segmentation on images of bone marrow preparations in information and measurement systems for diagnostics of acute leukemia

2020 ◽  
pp. 68-72
Author(s):  
V.G. Nikitaev ◽  
A.N. Pronichev ◽  
V.V. Dmitrieva ◽  
E.V. Polyakov ◽  
A.D. Samsonova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Acute Leukemia ◽  
White Blood Cell ◽  
Cell Separation ◽  
Large Scale ◽  
Bone Marrow Cells ◽  
Automated Analysis ◽  
Cell Segmentation ◽  
Measurement Systems

The issues of using of information and measurement systems based on processing of digital images of microscopic preparations for solving large-scale tasks of automating the diagnosis of acute leukemia are considered. The high density of leukocyte cells in the preparation (hypercellularity) is a feature of microscopic images of bone marrow preparations. It causes the proximity of cells to eachother and their contact with the formation of conglomerates. Measuring of the characteristics of bone marrow cells in such conditions leads to unacceptable errors (more than 50%). The work is devoted to segmentation of contiguous cells in images of bone marrow preparations. A method of cell separation during white blood cell segmentation on images of bone marrow preparations under conditions of hypercellularity of the preparation has been developed. The peculiarity of the proposed method is the use of an approach to segmentation of cell images based on the watershed method with markers. Key stages of the method: the formation of initial markers and builds the lines of watershed, a threshold binarization, shading inside the outline. The parameters of the separation of contiguous cells are determined. The experiment confirmed the effectiveness of the proposed method. The relative segmentation error was 5 %. The use of the proposed method in information and measurement systems of computer microscopy for automated analysis of bone marrow preparations will help to improve the accuracy of diagnosis of acute leukemia.

scholarly journals Ethnomedical uses, chemical constituents, and evidence-based pharmacological properties of Chenopodium ambrosioides L.: extensive overview

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Félicien Mushagalusa Kasali ◽  
Jonans Tusiimire ◽  
Justin Ntokamunda Kadima ◽  
Amon Ganafa Agaba
Keyword(s):  
Large Scale ◽  
Chemical Constituents ◽  
Main Body ◽  
Pharmacological Properties ◽  
Chenopodium Ambrosioides ◽  
Traditional Medicines ◽  
Plant Parts ◽  
Chemical Studies ◽  
Ethnomedicinal Uses ◽  
Significant Health

Abstract Background The Chenopodium genus is a plant family widely spread worldwide that includes various plant species reputed to possess several medicinal virtues in folk medicines. Chenopodium ambrosioides L. is among the most used plants in traditional medicines worldwide. This review aimed to highlight ethnomedicinal uses, phytochemical status, and pharmacological properties of C. ambrosioides L. Main body of the abstract The analysis of relevant data highlights various ethnomedicinal uses against human and veterinary diseases in forty countries. Most indications consisted of gastrointestinal tract dysfunctioning troubles and worms parasitemia. Around 330 chemical compounds have been identified in different plant parts, especially in its essential oil fractions (59.84%). However, only a few compounds—mainly monoterpenes and glycosides—have been isolated and characterized. Experimental pharmacological studies validated a large scale of significant health benefits. It appeared that many monoterpenes are antioxidant, insecticidal, trypanocidal, analgesic, antifungal, anti-inflammatory, anti-arthritic, acaricidal, amoebicidal, anthelmintic, anticancer, antibacterial, antidiabetic, antidiarrheal, antifertility, antifungal, anti-leishmanial, antimalarial, antipyretic, antisickling, antischistosomal, antiulcer, anxiolytic, immunomodulatory, molluscicidal, and vasorelaxant agents. Short conclusion Thus, the Chenopodium ambrosioides species necessitates further chemical studies to isolate and characterize new bioactive secondary metabolites and pharmacological investigations to precise the mechanisms of action before clinical trials.

scholarly journals Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1940
Author(s):  
Karl Michaëlsson ◽  
Susanna C. Larsson
Keyword(s):  
Bone Mineral Density ◽  
Confidence Interval ◽  
Bone Mineral ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Alpha Tocopherol ◽  
European Ancestry ◽  
Mineral Density ◽  
Standard Deviation Increase ◽  
A Genome

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

scholarly journals The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment

2021 ◽  
Vol 22 (12) ◽  
pp. 6422
Author(s):  
Caroline Pham ◽  
Noelia Muñoz-Martín ◽  
Elisabeth M. Lodder
Keyword(s):  
Cardiac Disease ◽  
Genetic Variants ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Regeneration ◽  
Cardiac Diseases ◽  
Supraventricular Arrhythmias ◽  
Clinical Perspective ◽  
Physiological Processes

In the two decades since the discovery of TNNI3K it has been implicated in multiple cardiac phenotypes and physiological processes. TNNI3K is an understudied kinase, which is mainly expressed in the heart. Human genetic variants in TNNI3K are associated with supraventricular arrhythmias, conduction disease, and cardiomyopathy. Furthermore, studies in mice implicate the gene in cardiac hypertrophy, cardiac regeneration, and recovery after ischemia/reperfusion injury. Several new papers on TNNI3K have been published since the last overview, broadening the clinical perspective of TNNI3K variants and our understanding of the underlying molecular biology. We here provide an overview of the role of TNNI3K in cardiomyopathy and arrhythmia covering both a clinical perspective and basic science advancements. In addition, we review the potential of TNNI3K as a target for clinical treatments in different cardiac diseases.

scholarly journals Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

2020 ◽  
Vol 4 (14) ◽  
pp. 3224-3233
Author(s):  
Paul J. Martin ◽  
David M. Levine ◽  
Barry E. Storer ◽  
Sarah C. Nelson ◽  
Xinyuan Dong ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Genetic Variants ◽  
Hematopoietic Cell Transplantation ◽  
Genome Wide Association Study ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
European Ancestry ◽  
A Genome ◽  
Grade 3 ◽  
Highly Correlated

Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

scholarly journals On the effects of membrane viscosity on transient red blood cell dynamics

Soft Matter ◽  
2020 ◽  
Vol 16 (26) ◽  
pp. 6191-6205 ◽  
Author(s):  
Fabio Guglietta ◽  
Marek Behr ◽  
Luca Biferale ◽  
Giacomo Falcucci ◽  
Mauro Sbragaglia
Keyword(s):  
Fluid Dynamics ◽  
Computational Fluid Dynamics ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Blood Circulation ◽  
Hydraulic Properties ◽  
Large Scale ◽  
Mechanical Response ◽  
Cell Dynamics ◽  
Membrane Viscosity

Computational Fluid Dynamics is currently used to design and improve the hydraulic properties of biomedical devices, wherein the large scale blood circulation needs to be simulated by accounting for the mechanical response of RBCs at the mesoscale.

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