scholarly journals Investigating the Impact of a Genome-Wide Supported Bipolar Risk Variant of MAD1L1 on the Human Reward System

2016 ◽  
Vol 41 (11) ◽  
pp. 2679-2687 ◽  
Author(s):  
Sarah Trost ◽  
Esther K Diekhof ◽  
Holger Mohr ◽  
Henning Vieker ◽  
Bernd Krämer ◽  
...  
Keyword(s):  
Reward System ◽  
Risk Variant ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

scholarly journals Further Evidence for the Impact of a Genome-Wide-Supported Psychosis Risk Variant in ZNF804A on the Theory of Mind Network

2013 ◽  
Vol 39 (5) ◽  
pp. 1196-1205 ◽  
Author(s):  
Sebastian Mohnke ◽  
Susanne Erk ◽  
Knut Schnell ◽  
Claudia Schütz ◽  
Nina Romanczuk-Seiferth ◽  
...  
Keyword(s):  
Theory Of Mind ◽  
Risk Variant ◽  
Genome Wide ◽  
A Genome ◽  
Psychosis Risk ◽  
The Impact

scholarly journals Machine-learning annotation of human splicing branchpoints

2016 ◽  
Author(s):  
Bethany Signal ◽  
Brian S Gloss ◽  
Marcel E Dinger ◽  
Timothy R Mercer
Keyword(s):  
Machine Learning ◽  
Learning Algorithm ◽  
Gene Splicing ◽  
Genetic Encoding ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Wide Scale ◽  
The Impact ◽  
Splicing Patterns

ABSTRACTBackgroundThe branchpoint element is required for the first lariat-forming reaction in splicing. However due to difficulty in experimentally mapping at a genome-wide scale, current catalogues are incomplete.ResultsWe have developed a machine-learning algorithm trained with empirical human branchpoint annotations to identify branchpoint elements from primary genome sequence alone. Using this approach, we can accurately locate branchpoints elements in 85% of introns in current gene annotations. Consistent with branchpoints as basal genetic elements, we find our annotation is unbiased towards gene type and expression levels. A major fraction of introns was found to encode multiple branchpoints raising the prospect that mutational redundancy is encoded in key genes. We also confirmed all deleterious branchpoint mutations annotated in clinical variant databases, and further identified thousands of clinical and common genetic variants with similar predicted effects.ConclusionsWe propose the broad annotation of branchpoints constitutes a valuable resource for further investigations into the genetic encoding of splicing patterns, and interpreting the impact of common- and disease-causing human genetic variation on gene splicing.

scholarly journals Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome

2021 ◽  
Vol 17 (9) ◽  
pp. e1009317
Author(s):  
Ilario De Toma ◽  
Cesar Sierra ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Differential Expression ◽  
Web Application ◽  
Meta Analysis ◽  
Chromosome 21 ◽  
Complex Disorders ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a “DS network”. We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in “clusters”, so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of “co-deregulation” involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created “metaDEA” an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.

scholarly journals Genome-Wide Copy Number Variation Association Study of Atrial Fibrillation Related Thromboembolic Stroke

2019 ◽  
Vol 8 (3) ◽  
pp. 332 ◽  
Author(s):  
Chia-Shan Hsieh ◽  
Pang-Shuo Huang ◽  
Sheng-Nan Chang ◽  
Cho-Kai Wu ◽  
Juey-Jen Hwang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Signaling Pathway ◽  
Copy Number ◽  
Genetic Factors ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Thromboembolic Stroke ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Atrial fibrillation (AF) is a common cardiac arrhythmia and is one of the major causes of ischemic stroke. In addition to the clinical factors such as CHADS2 or CHADS2-VASC score, the impact of genetic factors on the risk of thromboembolic stroke in patients with AF has been largely unknown. Single-nucleotide polymorphisms in several genomic regions have been found to be associated with AF. However, these loci do not contribute to all the genetic risks of AF or AF related thromboembolic risks, suggesting that there are other genetic factors or variants not yet discovered. In the human genome, copy number variations (CNVs) could also contribute to disease susceptibility. In the present study, we sought to identify CNVs determining the AF-related thromboembolic risk. Using a genome-wide approach in 109 patients with AF and thromboembolic stroke and 14,666 controls from the Taiwanese general population (Taiwan Biobank), we first identified deletions in chromosomal regions 1p36.32-1p36.33, 5p15.33, 8q24.3 and 19p13.3 and amplifications in 14q11.2 that were significantly associated with AF-related stroke in the Taiwanese population. In these regions, 148 genes were involved, including several microRNAs and long non-recoding RNAs. Using a pathway analysis, we found deletions in GNB1, PRKCZ, and GNG7 genes related to the alpha-adrenergic receptor signaling pathway that play a major role in determining the risk of an AF-related stroke. In conclusion, CNVs may be genetic predictors of a risk of a thromboembolic stroke for patients with AF, possibly pointing to an impaired alpha-adrenergic signaling pathway in the mechanism of AF-related thromboembolism.

scholarly journals Identification of novel sources of resistance to ascochyta blight in a collection of wild Cicer accessions

2020 ◽  
Author(s):  
Toby E. Newman ◽  
Silke Jacques ◽  
Christy Grime ◽  
Fiona L. Kamphuis ◽  
Robert C. Lee ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Ascochyta Blight ◽  
Ascochyta Rabiei ◽  
Sources Of Resistance ◽  
Highly Pathogenic ◽  
Cicer Echinospermum ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
Chickpea Cultivars

Chickpea production is constrained worldwide by the necrotrophic fungal pathogen Ascochyta rabiei, the causal agent of ascochyta blight (AB). In order to reduce the impact of this disease, novel sources of resistance are required in chickpea cultivars. Here, we screened a new collection of wild Cicer accessions for AB resistance and identified accessions resistant to multiple, highly pathogenic isolates. In addition to this, analyses demonstrated that some collection sites of Cicer echinospermum harbour predominantly resistant accessions, knowledge that can inform future collection missions. Furthermore, a genome-wide association study identified regions of the Cicer reticulatum genome associated with AB resistance and investigation of these regions identified candidate resistance genes. Taken together, these results can be utilised to enhance the resistance of chickpea cultivars to this globally yield-limiting disease.

Identification of ERG Specific Target Genes by Genome-Wide Screening in T-Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3788-3788
Author(s):  
Liliana H Mochmann ◽  
Konrad Neumann ◽  
Juliane Bock ◽  
Jutta Ortiz Tanchez ◽  
Arend Bohne ◽  
...  
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Specific Treatment ◽  
P Value ◽  
Dna Templates ◽  
Genome Wide ◽  
A Genome ◽  
On Chip ◽  
T Cell Leukemogenesis ◽  
The Impact

Abstract The Ets related gene, ERG, encodes a transcription factor with a vital role in hematopoiesis. Recent findings have shown that ERG knockout mice require a minimum of one functional allele to ensure embryonic blood development and adult stem cell maintenance. Moreover, it was earlier reported that enforced expression of ERG induced oncogenic transformation in 3T3 cells. Overexpression of ERG, observed in a subset of acute T-lymphoblastic and acute myeloid leukemia patients, was associated with an inferior outcome. However, the impact of ERG contributing to this unfavourable phenotype has yet to be determined, as downstream targets of ERG in leukemia remain unknown. Herein, we conducted a genome-wide analysis of ERG target genes in T-lymphoblastic leukemia. Chromatin immunoprecipitation-on-chip array (ChIP-on-chip) analyses were performed using two ERG specific antibodies for the enrichment of ERG-bound DNA templates in T-lymphoblastic leukemia cells (Jurkat) with input DNA or IgG precipitated DNA as controls. Enriched DNA templates and control DNA were differentially labelled and co-hybridized to high resolution promoter chip arrays with 50–75mer probes (770,000) representing 29,000 annotated human transcripts (NimbleGen). Based on two independent ChIP-on-chip assays, bioinformatic analysis (ACME) yielded statistically significant enriched peaks (using a sliding window of 1000 bp, and a P-value < 0.0001) identifying promoter regions of 365 potential ERG target genes. From these genes, clustering by functional annotation was performed using the DAVID database and subsequently genes related to leukemia were further selected for quantitative PCR validation. The design of promoter primers included the highly conserved ETS GGAA DNA binding site. Genes with greater than two-fold enrichment (ERG ChIP versus control) included WNT2 (17-fold), OLIG2 (14-fold), WNT11 (7-fold), CCND1 (5-fold), WNT9A (4-fold), CD7 (3-fold), EPO (3-fold), ERBB4 (3-fold), RPBJL (3-fold), TRADD (3-fold), PIWIL1 (2-fold), TNFRSF25 (2-fold), TWIST1 (2-fold), and HDAC4 (2-fold). Interestingly, enriched target genes involved in developmental processes (WNT2, WNT9A, WNT11, TWIST1, PIWIL1, ERBB4, and OLIG2) have shown oncogenic potential when mutated or overexpressed. Thus, we hypothesize that overexpression of ERG may contribute to T-cell leukemogenesis by the deregulation of these oncogenic targets. Further disclosure of ERG directed downstream pathways may contribute to the design of specific treatment strategies (such as WNT inhibitors) with particular effectiveness in ERG deregulated leukemia.

scholarly journals A genome-wide supported psychiatric risk variant inNCANinfluences brain function and cognitive performance in healthy subjects

2014 ◽  
Vol 36 (1) ◽  
pp. 378-390 ◽  
Author(s):  
Heidelore Raum ◽  
Bruno Dietsche ◽  
Arne Nagels ◽  
Stephanie H. Witt ◽  
Marcella Rietschel ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Brain Function ◽  
Healthy Subjects ◽  
Risk Variant ◽  
Genome Wide ◽  
A Genome

scholarly journals Re-analysis of a Genome-Wide Gene-By-Environment Interaction Study of Case Parent Trios, Adjusted for Population Stratification

2021 ◽  
Vol 11 ◽  
Author(s):  
Pulindu Ratnasekera ◽  
Brad McNeney
Keyword(s):  
East Asian ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multivitamin Supplementation ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
East Asian Ancestry

We investigate the impact of confounding on the results of a genome-wide association analysis by Beaty et al., which identified multiple single nucleotide polymorphisms that appeared to modify the effect of maternal smoking, alcohol consumption, or multivitamin supplementation on risk of cleft palate. The study sample of case-parent trios was primarily of European and East Asian ancestry, and the distribution of all three exposures differed by ancestral group. Such differences raise the possibility that confounders, rather than the exposures, are the risk modifiers and hence that the inference of gene-environment (G×E) interaction may be spurious. Our analyses generally confirmed the result of Beaty et al. and suggest the interaction G×E is driven by the European trios, whereas the East Asian trios were less informative.

scholarly journals The genomic impact of European colonization of the Americas

2019 ◽  
Author(s):  
Linda Ongaro ◽  
Marilia O. Scliar ◽  
Rodrigo Flores ◽  
Alessandro Raveane ◽  
Davide Marnetto ◽  
...  
Keyword(s):  
Gene Flow ◽  
Demographic History ◽  
Colonial Era ◽  
Genome Wide ◽  
A Genome ◽  
European Colonization ◽  
High Degree ◽  
The Impact ◽  
North And South America ◽  
North And South

AbstractThe human genetic diversity of the Americas has been shaped by several events of gene flow that have continued since the Colonial Era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored.Here we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected i) the genetic structure, ii) the admixture profile, iii) the demographic history and iv) sex-biased gene-flow dynamics, of the Americas.We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East and to specific regions of Africa.

scholarly journals Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1570 ◽  
Author(s):  
Emma-Jane Mallas ◽  
Francesco Carletti ◽  
Christopher A. Chaddock ◽  
James Woolley ◽  
Marco M. Picchioni ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
White Matter ◽  
Diffusion Tensor ◽  
Clinical Sample ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Risk Variant ◽  
White Matter Microstructure ◽  
Genome Wide ◽  
The Impact

Background.Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls.Methods.230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA.Results.As predicted, statistically significant reductions in FA across a widely distributed brain network (p< 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d= 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d= 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found.Discussion.We provide the first evidence in a predominantly Caucasian clinical sample, of an association betweenZNF804Ars1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.

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