scholarly journals TTC7B Emerges as a Novel Risk Factor for Ischemic Stroke Through the Convergence of Several Genome-Wide Approaches

2012 ◽  
Vol 32 (6) ◽  
pp. 1061-1072 ◽  
Author(s):  
Tiago Krug ◽  
João Paulo Gabriel ◽  
Ricardo Taipa ◽  
Benedita V Fonseca ◽  
Sophie Domingues-Montanari ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Differentially Expressed ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Peripheral Blood Mononuclear ◽  
Pathogenic Potential ◽  
Novel Approach ◽  
Genome Wide

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5–intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

scholarly journals IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction

2013 ◽  
Vol 210 (6) ◽  
pp. 1109-1116 ◽  
Author(s):  
Stéphanie Bibert ◽  
Thierry Roger ◽  
Thierry Calandra ◽  
Murielle Bochud ◽  
Andreas Cerny ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Association Studies ◽  
Antiviral Agents ◽  
Genetic Regulation ◽  
World Population ◽  
Genome Wide Association Studies ◽  
Peripheral Blood Mononuclear ◽  
Genome Wide ◽  
Inducible Protein ◽  
Improve Patient Management

Approximately 3% of the world population is chronically infected with the hepatitis C virus (HCV), with potential development of cirrhosis and hepatocellular carcinoma. Despite the availability of new antiviral agents, treatment remains suboptimal. Genome-wide association studies (GWAS) identified rs12979860, a polymorphism nearby IL28B, as an important predictor of HCV clearance. We report the identification of a novel TT/-G polymorphism in the CpG region upstream of IL28B, which is a better predictor of HCV clearance than rs12979860. By using peripheral blood mononuclear cells (PBMCs) from individuals carrying different allelic combinations of the TT/-G and rs12979860 polymorphisms, we show that induction of IL28B and IFN-γ–inducible protein 10 (IP-10) mRNA relies on TT/-G, but not rs12979860, making TT/-G the only functional variant identified so far. This novel step in understanding the genetic regulation of IL28B may have important implications for clinical practice, as the use of TT/G genotyping instead of rs12979860 would improve patient management.

scholarly journals The migraine–stroke connection: A genetic perspective

Cephalalgia ◽  
2015 ◽  
Vol 36 (7) ◽  
pp. 658-668 ◽  
Author(s):  
Rainer Malik ◽  
Bendik Winsvold ◽  
Eva Auffenberg ◽  
Martin Dichgans ◽  
Tobias Freilinger
Keyword(s):  
Ischemic Stroke ◽  
Vascular Disease ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Familial Hemiplegic Migraine ◽  
Artery Dissection ◽  
Cervical Artery Dissection ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Disease Manifestation

Background A complex relationship between migraine and vascular disease has long been recognized. The pathophysiological basis underlying this correlation is incompletely understood. Aim The aim of this review is to focus on the migraine–vascular disorders connection from a genetic perspective, illustrating potentially shared (molecular) mechanisms. Results We first summarize the clinical presentation and genetic basis of CADASIL and other monogenic vascular syndromes with migraine as a prominent disease manifestation. Based on data from transgenic mouse models for familial hemiplegic migraine, we then discuss cortical spreading depression as a potential mechanistic link between migraine and ischemic stroke. Finally, we review data from genome-wide association studies, with a focus on overlapping findings with cervical artery dissection, ischemic stroke in general and cardiovascular disease. Conclusion A wealth of data supports a genetic link between migraine and vascular disease. Based on growing high-throughput data-sets, new genotyping techniques and in-depth phenotyping, further insights are expected for the future.

scholarly journals A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn’s Disease in Japanese Individuals

2018 ◽  
Vol 13 (5) ◽  
pp. 648-658 ◽  
Author(s):  
Yoichi Kakuta ◽  
Yosuke Kawai ◽  
Takeo Naito ◽  
Atsushi Hirano ◽  
Junji Umeno ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Genome Wide Association ◽  
Effector Memory ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract Background and Aims Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn’s disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10−26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10−19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10−6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10−8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions RAP1A is a novel susceptibility locus for CD in the Japanese population.

scholarly journals Comment on ‘Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets’ by Lam et al.

2018 ◽  
Vol 21 (2) ◽  
pp. 84-88 ◽  
Author(s):  
W. David Hill
Keyword(s):  
Genetic Information ◽  
Drug Targets ◽  
Large Scale ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Nootropic Drug ◽  
Genome Wide

Intelligence and educational attainment are strongly genetically correlated. This relationship can be exploited by Multi-Trait Analysis of GWAS (MTAG) to add power to Genome-wide Association Studies (GWAS) of intelligence. MTAG allows the user to meta-analyze GWASs of different phenotypes, based on their genetic correlations, to identify association's specific to the trait of choice. An MTAG analysis using GWAS data sets on intelligence and education was conducted by Lam et al. (2017). Lam et al. (2017) reported 70 loci that they described as ‘trait specific’ to intelligence. This article examines whether the analysis conducted by Lam et al. (2017) has resulted in genetic information about a phenotype that is more similar to education than intelligence.

Biomarkers for Comorbidities in Psoriasis: A Report from the Grappa 2011 Annual Meeting

2012 ◽  
Vol 39 (11) ◽  
pp. 2193-2195 ◽  
Author(s):  
DAFNA D. GLADMAN
Keyword(s):  
Psoriatic Arthritis ◽  
Annual Meeting ◽  
Research Team ◽  
Association Studies ◽  
Differentially Expressed ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Current Database ◽  
And Cartilage

Biomarkers are being recognized that will help identify patients with psoriasis who may be destined to develop psoriatic arthritis (PsA). Recent genome-wide association studies have identified genes that are common to both psoriasis and PsA, as well as differentially expressed in the 2 conditions. Further, biomarkers of inflammation and cartilage can differentiate between patients with PsA and those with psoriasis without arthritis. An overview of these biomarkers was presented at the 2011 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Additionally, a report was presented from the current database of the International Psoriasis and Psoriatic Arthritis Research Team, a group of dermatologists and rheumatologists with the objective to improve the lives of patients with psoriasis and PsA.

scholarly journals Controlling the Rate of GWAS False Discoveries

2016 ◽  
Author(s):  
Damian Brzyski ◽  
Christine B. Peterson ◽  
Piotr Sobczyk ◽  
Emmanuel J. Candés ◽  
Malgorzata Bogdan ◽  
...  
Keyword(s):  
Association Studies ◽  
Genetic Association Studies ◽  
R Package ◽  
Dependence Structure ◽  
Genome Wide Association Studies ◽  
Genomic Locus ◽  
Novel Approach ◽  
Genome Wide ◽  
Single Marker ◽  
False Discoveries

AbstractWith the rise of both the number and the complexity of traits of interest, control of the false discovery rate (FDR) in genetic association studies has become an increasingly appealing and accepted target for multiple comparison adjustment. While a number of robust FDR controlling strategies exist, the nature of this error rate is intimately tied to the precise way in which discoveries are counted, and the performance of FDR controlling procedures is satisfactory only if there is a one-to-one correspondence between what scientists describe as unique discoveries and the number of rejected hypotheses. The presence of linkage disequilibrium between markers in genome-wide association studies (GWAS) often leads researchers to consider the signal associated to multiple neighboring SNPs as indicating the existence of a single genomic locus with possible influence on the phenotype. This a posteriori aggregation of rejected hypotheses results in inflation of the relevant FDR. We propose a novel approach to FDR control that is based on pre-screening to identify the level of resolution of distinct hypotheses. We show how FDR controlling strategies can be adapted to account for this initial selection both with theoretical results and simulations that mimic the dependence structure to be expected in GWAS. We demonstrate that our approach is versatile and useful when the data are analyzed using both tests based on single marker and multivariate regression. We provide an R package that allows practitioners to apply our procedure on standard GWAS format data, and illustrate its performance on lipid traits in the NFBC66 cohort study.

scholarly journals emeraLD: Rapid Linkage Disequilibrium Estimation with Massive Data Sets

2018 ◽  
Author(s):  
Corbin Quick ◽  
Christian Fuchsberger ◽  
Daniel Taliun ◽  
Gonçalo Abecasis ◽  
Michael Boehnke ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Association Studies ◽  
Random Access ◽  
Supplementary Information ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Genome Wide ◽  
Wide Range ◽  
Supplementary Material

AbstractSummaryEstimating linkage disequilibrium (LD) is essential for a wide range of summary statistics-based association methods for genome-wide association studies (GWAS). Large genetic data sets, e.g. the TOPMed WGS project and UK Biobank, enable more accurate and comprehensive LD estimates, but increase the computational burden of LD estimation. Here, we describe emeraLD (Efficient Methods for Estimation and Random Access of LD), a computational tool that leverages sparsity and haplotype structure to estimate LD orders of magnitude faster than existing tools.Availability and ImplementationemeraLD is implemented in C++, and is open source under GPLv3. Source code, documentation, an R interface, and utilities for analysis of summary statistics are freely available at http://github.com/statgen/[email protected] informationSupplementary data are available at Bioinformatics online.

scholarly journals A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells

2020 ◽  
Vol 9 (3) ◽  
pp. 625
Author(s):  
Elia Gil-Varea ◽  
Maria Fedetz ◽  
Herena Eixarch ◽  
Nino Spataro ◽  
Luisa María Villar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Luciferase Reporter ◽  
Regulatory Sequences ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Peripheral Blood Mononuclear

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.

scholarly journals Replication of Top Loci From COL4A1/2 Associated With White Matter Hyperintensity Burden in Patients With Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3751-3755
Author(s):  
Jiang Li ◽  
Vida Abedi ◽  
Ramin Zand ◽  
Christoph J. Griessenauer ◽  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Ischemic Stroke ◽  
Odds Ratio ◽  
Association Studies ◽  
Genome Wide Association ◽  
White Matter Hyperintensity ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Genome Wide

Background and Purpose: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. Methods: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. Results: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 ( COL4A2 ) and rs3744028 ( TRIM65 ), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P =0.001 for rs9515201; β=0.094 and P =0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P =7.74×10 − 4 for rs9515201; odds ratio=1.53, P =0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele ( P =0.019). Conclusions: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.

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