scholarly journals Pathway analysis of genome-wide data improves warfarin dose prediction

BMC Genomics ◽  
2013 ◽  
Vol 14 (S3) ◽  
Author(s):  
Roxana Daneshjou ◽  
Nicholas P Tatonetti ◽  
Konrad J Karczewski ◽  
Hersh Sagreiya ◽  
Stephane Bourgeois ◽  
...  
Keyword(s):  
Pathway Analysis ◽  
Warfarin Dose ◽  
Dose Prediction ◽  
Genome Wide ◽  
Genome Wide Data

The Negative Impact of Biological Variation in the Effect and Clearance of Warfarin on Methods for Prediction of Dose Requirements

1986 ◽  
Vol 56 (03) ◽  
pp. 371-375 ◽  
Author(s):  
Peretz Weiss ◽  
Hillel Halkin ◽  
Shlomo Almog
Keyword(s):  
Individual Variation ◽  
Negative Impact ◽  
Warfarin Dose ◽  
Empirical Therapy ◽  
Maintenance Phase ◽  
Individual Variability ◽  
Dose Prediction ◽  
Group I ◽  
Over Time ◽  
Variance Explained

SummaryWithin-individual variation over time in the clearance (Cl) and effect (PT%) of warfarin, was measured in 25 inpatients (group I) studied after standard single or individualized split loading doses and 1-3 times (n = 16) 8-16 weeks later during maintenance. Mean Cl (2.5 α 0.9 ml/min) was similar in both phases but significant changes occurred in 6/16 patients, exceeding those expected from within-individual variation alone (defined by its 95% tolerance limits -24% to +62%). Initial PT% (21 α 5) was unaffected by dosing schedule, total or free plasma warfarin, varying between patients by only 18-24%. Mean initial and maintenance dose-PT% ratios (8.2 mg/d: 21% and 4.1 mg/d: 40%) were similar but significant changes in sensitivity to warfarin occurred in 4/16 patients. In group I and 64 other outpatients on maintenance therapy, between-individual variability was 36-52% for Cl and 49-56% for effect. PT% correlated best (r = 0.56) with free and total plasma warfarin but poorly with dose (r = 0.29), with only 30% of PT% variance explained at best, due to high between patient variability.Warfarin dose prediction whether based on extrapolation from initial effects to the maintenance phase, or on iterative methods not allowing for between- or within-patient variation in warfarin clearance or effect which may occur independently over time, have not improved on empirical therapy. This, due to the elements of biological variability as well as the intricacy of the warfarin - prothrombin complex interaction not captured by any kinetic-dynamic model used for prediction to date.

scholarly journals Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9036
Author(s):  
Sara Saez-Atienzar ◽  
Sara Bandres-Ciga ◽  
Rebekah G. Langston ◽  
Jonggeol J. Kim ◽  
Shing Wan Choi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
Genome Wide Data ◽  
Data Driven Approach ◽  
Single Nucleus ◽  
Lateral Sclerosis

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types.

scholarly journals Variation in VKORC1 Is Associated with Vascular Dementia

2021 ◽  
Vol 80 (3) ◽  
pp. 1329-1337
Author(s):  
Jure Mur ◽  
Daniel L. McCartney ◽  
Daniel I. Chasman ◽  
Peter M. Visscher ◽  
Graciela Muniz-Terrera ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Vascular Dementia ◽  
Genetic Variant ◽  
Warfarin Dose ◽  
Uk Biobank ◽  
Parental History ◽  
Genome Wide ◽  
History Of ◽  
First Time ◽  
The Relationship

Background: The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus. Objective: Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk. Methods: We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use. Results: Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.

scholarly journals Ancient genomic time transect from the Central Asian Steppe unravels the history of the Scythians

2021 ◽  
Vol 7 (13) ◽  
pp. eabe4414
Author(s):  
Guido Alberto Gnecchi-Ruscone ◽  
Elmira Khussainova ◽  
Nurzhibek Kahbatkyzy ◽  
Lyazzat Musralina ◽  
Maria A. Spyrou ◽  
...  
Keyword(s):  
Bronze Age ◽  
Iron Age ◽  
Gene Pools ◽  
Social Rules ◽  
Eurasian Steppe ◽  
Central Asian ◽  
Genome Wide ◽  
Genome Wide Data ◽  
History Of ◽  
First Millennium

The Scythians were a multitude of horse-warrior nomad cultures dwelling in the Eurasian steppe during the first millennium BCE. Because of the lack of first-hand written records, little is known about the origins and relations among the different cultures. To address these questions, we produced genome-wide data for 111 ancient individuals retrieved from 39 archaeological sites from the first millennia BCE and CE across the Central Asian Steppe. We uncovered major admixture events in the Late Bronze Age forming the genetic substratum for two main Iron Age gene-pools emerging around the Altai and the Urals respectively. Their demise was mirrored by new genetic turnovers, linked to the spread of the eastern nomad empires in the first centuries CE. Compared to the high genetic heterogeneity of the past, the homogenization of the present-day Kazakhs gene pool is notable, likely a result of 400 years of strict exogamous social rules.

scholarly journals Genome diversity in Ukraine

GigaScience ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Taras K Oleksyk ◽  
Walter W Wolfsberger ◽  
Alexandra M Weber ◽  
Khrystyna Shchubelka ◽  
Olga T Oleksyk ◽  
...  
Keyword(s):  
Sequence Data ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
High Coverage ◽  
Genome Data ◽  
New Information ◽  
Genome Wide ◽  
Public Data ◽  
Genome Wide Data ◽  
Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

scholarly journals Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry

Nature ◽  
2021 ◽  
Vol 592 (7853) ◽  
pp. 253-257 ◽  
Author(s):  
Mateja Hajdinjak ◽  
Fabrizio Mafessoni ◽  
Laurits Skov ◽  
Benjamin Vernot ◽  
Alexander Hübner ◽  
...  
Keyword(s):  
Family History ◽  
East Asia ◽  
Late Pleistocene ◽  
Modern Human ◽  
Human Migration ◽  
Upper Palaeolithic ◽  
Modern Humans ◽  
Genome Wide ◽  
Genome Wide Data

AbstractModern humans appeared in Europe by at least 45,000 years ago1–5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.

Sign in / Sign up

Export Citation Format

Share Document