Bayesian network analysis of plasma microRNA sequencing data in patients with venous thrombosis

Abstract MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P < 5 × 10−8, some of these associations pertaining to thrombosis associated mechanisms. In conclusion, this study provides novel data about the impact of miRNAs’ variability in haemostasis and new arguments supporting the association of few miRNAs with the risk of recurrence in patients with venous thrombosis.

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Finding genetic variants in plants without complete genomes

10.1101/818096 ◽

2019 ◽

Cited By ~ 2

Author(s):

Yoav Voichek ◽

Detlef Weigel

Keyword(s):

Genetic Variants ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Structural Variants ◽

Sequencing Data ◽

New Associations ◽

Maize Populations ◽

Genome Wide ◽

Genomic Regions

AbstractStructural variants and presence/absence polymorphisms are common in plant genomes, yet they are routinely overlooked in genome-wide association studies (GWAS). Here, we expand the genetic variants detected in GWAS to include major deletions, insertions, and rearrangements. We first use raw sequencing data directly to derive short sequences, k-mers, that mark a broad range of polymorphisms independently of a reference genome. We then link k-mers associated with phenotypes to specific genomic regions. Using this approach, we re-analyzed 2,000 traits measured in Arabidopsis thaliana, tomato, and maize populations. Associations identified with k-mers recapitulate those found with single-nucleotide polymorphisms (SNPs), however, with stronger statistical support. Moreover, we identified new associations with structural variants and with regions missing from reference genomes. Our results demonstrate the power of performing GWAS before linking sequence reads to specific genomic regions, which allow detection of a wider range of genetic variants responsible for phenotypic variation.

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Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

International Journal of Endocrinology ◽

10.1155/2017/6437542 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Lijun Wu ◽

Liwang Gao ◽

Xiaoyuan Zhao ◽

Meixian Zhang ◽

Jianxin Wu ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Multiple Testing ◽

Association Studies ◽

Statistical Significance ◽

Additive Model ◽

Recessive Model ◽

Chinese Children ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P=0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

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Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2227 ◽

2011 ◽

Vol 96 (6) ◽

pp. E953-E957 ◽

Cited By ~ 21

Author(s):

Mark A. Sarzynski ◽

Peter Jacobson ◽

Tuomo Rankinen ◽

Björn Carlsson ◽

Lars Sjöström ◽

...

Keyword(s):

Bariatric Surgery ◽

Weight Loss ◽

Candidate Genes ◽

Association Studies ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cross Sectional ◽

Time Points ◽

Obese Subjects

Context and Objective: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study. Methods: Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance. Results: In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2–4.2% (P < 10−14) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R2 = 0.4–1.1%; 3.8 × 10−6 < P < 3 × 10−3), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10−4 < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C. Conclusions: SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

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The use of genomic data and imputation methods in dairy cattle breeding

Czech Journal of Animal Science ◽

10.17221/83/2020-cjas ◽

2020 ◽

Vol 65 (No. 12) ◽

pp. 445-453

Author(s):

Anita Klímová ◽

Eva Kašná ◽

Karolína Machová ◽

Michaela Brzáková ◽

Josef Přibyl ◽

...

Keyword(s):

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Phenotypic Data ◽

Single Nucleotide ◽

Imputation Methods ◽

Genome Wide ◽

Dairy Cattle Breeding ◽

Combine Information

The inclusion of animal genotype data has contributed to the development of genomic selection. Animals are selected not only based on pedigree and phenotypic data but also on the basis of information about their genotypes. Genomic information helps to increase the accuracy of selection of young animals and thus enables a reduction of the generation interval. Obtaining information about genotypes in the form of SNPs (single nucleotide polymorphisms) has led to the development of new chips for genotyping. Several methods of genomic comparison have been developed as a result. One of the methods is data imputation, which allows the missing SNPs to be calculated using low-density chips to high-density chips. Through imputations, it is possible to combine information from diverse sets of chips and thus obtain more information about genotypes at a lower cost. Increasing the amount of data helps increase the reliability of predicting genomic breeding values. Imputation methods are increasingly used in genome-wide association studies. When classical genotyping and genome-wide sequencing data are combined, this option helps to increase the chances of identifying loci that are associated with economically significant traits.

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Snp Characteristics and Validation Success in Genome Wide Association Studies

10.21203/rs.3.rs-704899/v1 ◽

2021 ◽

Author(s):

Olga Gorlova ◽

Xiangjun Xiao ◽

Spiridon Tsavachidis ◽

Christopher I. Amos ◽

Ivan P. Gorlov

Keyword(s):

Success Rate ◽

Association Studies ◽

Statistical Significance ◽

Positive Association ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Multivariable Logistic Regression Model ◽

Functional Studies ◽

Genome Wide

Abstract Genome wide association studies (GWASs) have identified tens of thousands of single nucleotide polymorphisms (SNPs) associated with human diseases and characteristics. A significant fraction of GWAS findings can be false positives. The gold standard for true positives is an independent validation. The goal of this study was to identify SNP features associated with validation success. Summary statistics from the Catalog of Published GWASs were used in the analysis. Since our goal was an analysis of reproducibility, we focused on the diseases/phenotypes targeted by at least 10 GWASs. GWASs were arranged in discovery-validation pairs based on the time of publication, with the discovery GWAS published before validation. We used four definitions of the validation success that differ by stringency. Associations of SNP features with validation success were consistent across the definitions. The strongest predictor of SNP validation was the level of statistical significance in the discovery GWAS. The magnitude of the effect size was associated with validation success in a non-linear manner. SNPs with risk allele frequencies in the range 30-70% showed a higher validation success rate compared to rarer or more common SNPs. Missense, 5’UTR, stop gained, and SNPs located in transcription factor binding sites had a higher validation success rate compared to intergeneic, intronic, or synonymous SNPs. There was a positive association between validation success and the level of evolutionary conservation of the sites. In addition, validation success was higher when discovery and validation GWASs targeted the same ethnicity. All predictors of validation success remained significant in a multivariable logistic regression model indicating their independent contribution. To conclude, we identified SNP features predicting validation success of GWAS hits. These features can be used to select SNPs for validation and downstream functional studies.

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The role of polymorphic ERAP1 in autoinflammatory disease

Bioscience Reports ◽

10.1042/bsr20171503 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 15

Author(s):

Emma Reeves ◽

Edward James

Keyword(s):

Single Nucleotide Polymorphisms ◽

Autoinflammatory Disease ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Cell Functions ◽

The Impact

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

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Reference SVA insertion polymorphisms are associated with dopaminergic degeneration in Parkinson’s Disease and differential gene expression in the PPMI cohort

10.21203/rs.3.rs-41600/v1 ◽

2020 ◽

Author(s):

Abigail L Pfaff ◽

Vivien J. Bubb ◽

John P. Quinn ◽

Sulev Koks

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differential Gene Expression ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Genome Wide ◽

Differential Gene

Abstract Background: The development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. The majority of studies investigating the genetic component of complex diseases, including PD, have focused on single nucleotide polymorphisms as this enables genome wide analysis of a large number of samples. Genome wide association studies have been crucial in identifying PD risk variants, however a large proportion of the heritability of PD remains to be identified. To investigate the component of PD that may involve complex genetic variants we characterised SINE-VNTR-Alus (SVAs), a retrotransposon known to affect gene expression, in the Parkinson’s Progression Markers Initiative (PPMI) cohort.Results: Utilising whole genome sequencing from the PPMI cohort that consisted of 179 healthy controls, 371 individuals with PD and 58 individuals classified as SWEDD (scans without evidence of dopaminergic deficit) we genotyped SVAs in the reference genome for their presence or absence identifying 81 such SVAs. Seven of these SVAs were associated with progression of the disease, including four whose specific genotypes were linked to an increase in the gradient of dopaminergic loss when comparing the caudate to putamen from DaTscan imaging analysis. These seven SVAs also demonstrated regulatory properties as they were associated with differential gene expression in whole blood RNA sequencing data.Conclusion: This study highlights the importance of addressing variation of SVAs and potentially other types of retrotransposons in PD genetics, furthermore these SVA elements should be considered as regulatory domains that could play a role in disease progression.

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Mapping gene and gene pathways associated with coronary artery disease: a CARDIoGRAM exome and multi-ancestry UK biobank analysis

Scientific Reports ◽

10.1038/s41598-021-95637-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Praveen Hariharan ◽

Josée Dupuis

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Association Studies ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Single Nucleotide Variants ◽

Significance Threshold ◽

Genome Wide ◽

Artery Disease

AbstractCoronary artery disease (CAD) genome-wide association studies typically focus on single nucleotide variants (SNVs), and many potentially associated SNVs fail to reach the GWAS significance threshold. We performed gene and pathway-based association (GBA) tests on publicly available Coronary ARtery DIsease Genome wide Replication and Meta-analysis consortium Exome (n = 120,575) and multi ancestry pan UK Biobank study (n = 442,574) summary data using versatile gene-based association study (VEGAS2) and Multi-marker analysis of genomic annotation (MAGMA) to identify novel genes and pathways associated with CAD. We included only exonic SNVs and excluded regulatory regions. VEGAS2 and MAGMA ranked genes and pathways based on aggregated SNV test statistics. We used Bonferroni corrected gene and pathway significance threshold at 3.0 × 10–6 and 1.0 × 10–5, respectively. We also report the top one percent of ranked genes and pathways. We identified 17 top enriched genes with four genes (PCSK9, FAM177, LPL, ARGEF26), reaching statistical significance (p ≤ 3.0 × 10–6) using both GBA tests in two GWAS studies. In addition, our analyses identified ten genes (DUSP13, KCNJ11, CD300LF/RAB37, SLCO1B1, LRRFIP1, QSER1, UBR2, MOB3C, MST1R, and ABCC8) with previously unreported associations with CAD, although none of the single SNV associations within the genes were genome-wide significant. Among the top 1% non-lipid pathways, we detected pathways regulating coagulation, inflammation, neuronal aging, and wound healing.

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Separating the contributions of SLC26A9 and CFTR to anion secretion in primary human bronchial epithelia (HBE)

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00563.2020 ◽

2021 ◽

Author(s):

Mads B Larsen ◽

Jeannie J Choi ◽

Xiaohui Wang ◽

Michael M Myerburg ◽

Raymond A Frizzell ◽

...

Keyword(s):

Cystic Fibrosis ◽

Association Studies ◽

Primary Source ◽

Airway Disease ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Anion Secretion ◽

Anion Transporter ◽

Bronchial Epithelia ◽

The Impact

Aberrant anion secretion across the bronchial epithelium is associated with airway disease, most notably in cystic fibrosis. While the cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as the primary source of airway anion secretion, alternative anion transport mechanisms play a contributing role. An alternative anion transporter of growing interest is SLC26A9, a constitutively active chloride channel which has been shown to interact with CFTR and may also contribute to bicarbonate secretion. Interest in SLC26A9 has been fueled by genome-wide association studies which suggest it is a significant modifier of CF disease severity. In spite of this growing evidence that SLC26A9 plays an important role in the airway, its presence and function in bronchial epithelia remains poorly understood, in part because its activity is difficult to separate from the activity of CFTR. Here we present results using primary, human bronchial epithelia (HBE) from multiple patient sources to confirm that SLC26A9 mRNA is present in HBE, and that its constitutive channel activity is unaffected by knock down of CFTR. Furthermore, SLC26A9 and CFTR show differential responses to common inhibitors of anion secretion. Finally, we assess the impact of bicarbonate on the activity of SLC26A9 and CFTR. These results confirm that SLC26A9 is the primary source of constitutive anion secretion across HBE, and should inform future studies focused on activation of SLC26A9 as an alternative anion channel in CF. These results should provide a strong foundation to investigate how single nucleotide polymorphisms in SLC26A9 modulate airway disease.

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The MIR137 VNTR rs58335419 Is Associated With Cognitive Impairment in Schizophrenia and Altered Cortical Morphology

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa123 ◽

2020 ◽

Author(s):

Ebrahim Mahmoudi ◽

Joshua R Atkins ◽

Yann Quidé ◽

William R Reay ◽

Heath M Cairns ◽

...

Keyword(s):

Association Studies ◽

Variable Number Tandem Repeat ◽

Variable Number ◽

Brain Morphology ◽

Whole Genome Sequencing Data ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Genome Wide ◽

Cortical Morphology

Abstract Genome-wide association studies (GWAS) of schizophrenia have strongly implicated a risk locus in close proximity to the gene for miR-137. While there are candidate single-nucleotide polymorphisms (SNPs) with functional implications for the microRNA’s expression encompassed by the common haplotype tagged by rs1625579, there are likely to be others, such as the variable number tandem repeat (VNTR) variant rs58335419, that have no proxy on the SNP genotyping platforms used in GWAS to date. Using whole-genome sequencing data from schizophrenia patients (n = 299) and healthy controls (n = 131), we observed that the MIR137 4-repeats VNTR (VNTR4) variant was enriched in a cognitive deficit subtype of schizophrenia and associated with altered brain morphology, including thicker left inferior temporal gyrus and deeper right postcentral sulcus. These findings suggest that the MIR137 VNTR4 may impact neuroanatomical development that may, in turn, influence the expression of more severe cognitive symptoms in patients with schizophrenia.

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