scholarly journals Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness

2016 ◽  
Vol 47 (4) ◽  
pp. 1072-1081 ◽  
Author(s):  
Marie-Hélène Dizier ◽  
Rachel Nadif ◽  
Patricia Margaritte-Jeannin ◽  
Sheila J. Barton ◽  
Chloé Sarnowski ◽  
...  
Keyword(s):  
Significant Interaction ◽  
Multiple Testing ◽  
Bronchial Hyperresponsiveness ◽  
Homogeneity Test ◽  
Nucleotide Polymorphisms ◽  
Linear Interaction ◽  
Genome Wide ◽  
Respiratory Cilia ◽  
Family Based ◽  
Log Linear

A previous genome-wide linkage scan of bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families, performed in the presence of a gene×early-life environmental tobacco smoke (ETS) exposure interaction, showed the strongest interaction in the 17p11 region where linkage was detected only among unexposed siblings. Our goal was to conduct fine-scale mapping of 17p11 to identify single nucleotide polymorphisms (SNPs) interacting with ETS that influence BHR.Analyses were performed in 388 French EGEA asthmatic families, using a two-step strategy: 1) selection of SNPs displaying family-based association test (FBAT) association signals (p≤0.01) with BHR in unexposed siblings, and 2) a FBAT homogeneity test between exposed and unexposed siblings plus a robust log-linear interaction test.A single SNP reached the threshold (p≤3×10−3) for significant interaction with ETS using both interaction tests, after accounting for multiple testing. Results were replicated in 253 French-Canadian families, but not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs to DNAH9 (dynein, axonemal, heavy chain 9), a promising candidate gene involved in respiratory cilia mobility and associated with primary ciliary dyskinesia, a disease associated with abnormalities of pulmonary function.

A family-based genome-wide association study reveals an association of spondyloarthritis with MAPK14

2016 ◽  
Vol 76 (1) ◽  
pp. 310-314 ◽  
Author(s):  
Félicie Costantino ◽  
Alice Talpin ◽  
Roula Said-Nahal ◽  
Ariane Leboime ◽  
Elena Zinovieva ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Gwas Study ◽  
Genome Wide ◽  
Multiplex Families ◽  
Family Based

ObjectiveMore than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA.Methods906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations.Results43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10−4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10−7). Such association appeared to be independent of HLA-B27.ConclusionsWe report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.

scholarly journals An Enrichment Analysis for Cardiometabolic Traits Suggests Non-Random Assignment of Genes to microRNAs

2018 ◽  
Vol 19 (11) ◽  
pp. 3666 ◽  
Author(s):  
Rima Mustafa ◽  
Mohsen Ghanbari ◽  
Marina Evangelou ◽  
Abbas Dehghan
Keyword(s):  
Multiple Testing ◽  
Target Genes ◽  
Association Studies ◽  
Enrichment Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Random Assignment ◽  
Genome Wide ◽  
Cardiometabolic Disorders ◽  
Cardiometabolic Traits

MicroRNAs (miRNAs) regulate the expression of the majority of genes. However, it is not known whether they regulate genes in random or are organized according to their function. To this end, we chose cardiometabolic disorders as an example and investigated whether genes associated with cardiometabolic disorders are regulated by a random set of miRNAs or a limited number of them. Single-nucleotide polymorphisms (SNPs) reaching genome-wide level significance were retrieved from most recent genome-wide association studies on cardiometabolic traits, which were cross-referenced with Ensembl to identify related genes and combined with miRNA target prediction databases (TargetScan, miRTarBase, or miRecords) to identify miRNAs that regulate them. We retrieved 520 SNPs, of which 355 were intragenic, corresponding to 304 genes. While we found a higher proportion of genes reported from all GWAS that were predicted targets for miRNAs in comparison to all protein-coding genes (75.1%), the proportion was even higher for cardiometabolic genes (80.6%). Enrichment analysis was performed within each database. We found that cardiometabolic genes were over-represented in target genes for 29 miRNAs (based on TargetScan) and 3 miRNAs (miR-181a, miR-302d and miR-372) (based on miRecords) after Benjamini-Hochberg correction for multiple testing. Our work provides evidence for non-random assignment of genes to miRNAs and supports the idea that miRNAs regulate sets of genes that are functionally related.

Abstract P361: The First Genome-Wide Association Study (GWAS) of GlycA, an NMR-Derived Marker of Inflammation, Reveals Associations With a Variant in the Intron of TXNL4B Across Two Cohorts

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Alexis C Frazier-Wood ◽  
Stella Aslibekyan ◽  
Ingrid B Borecki ◽  
Jose M Ordovas ◽  
Jerome I Rotter ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Multiple Testing ◽  
Genome Wide Association Study ◽  
Smoking Status ◽  
Lipid Lowering ◽  
Metabolic Dysfunction ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Markers Of Inflammation ◽  
Genome Wide

Markers of inflammation reflect metabolic dysfunction and may predict incident cardiovascular events. GlycA is a new NMR-derived plasma marker of inflammation. Our goal was to undertake first characterization of the genetic variants associated with fasting GlycA, to elucidate the pathways from genes to inflammation. We completed a GWAS in the Caucasian-ancestry population of The Multi-Ethnic Study of Atherosclerosis (MESA; N=2,520; 48% male, mean age 62.7 y). We specified linear regressions models with GlycA as the outcome, and ~2.5 million single nucleotide polymorphisms (SNPs) directly genotyped or imputed from HapMap as the predictors in separate models; all models additionally controlled for age, gender, alcohol intake (g/day), smoking status (yes / no) and 4 principal components of population structure. In MESA, 5 SNPs reached genome-wide levels of significance (P<10 -8 ; Table 1). Forty six SNPs reached a ‘discovery threshold’ of P<10 -5 in MESA, but only one (rs217181; minor allele frequency = .18) replicated in the Genetics of Lipid Lowering Drug Network (GOLDN; N=817; 48% male, mean age=48.8 years) after an FDR multiple testing correction. Rs217181 is located in the intron of TXNL4B , thioredoxin-like 4B, and in close proximity to HP , Haptoglobin , and HPR, Haptoglobin-related Protein . Rs217181 has been validated as associating with levels of haptoglobin protein. Haptoglobin is released by the liver and reduces hemoglobin’s oxidative activity. Our data suggests that rs217181 is involved in inflammation status, and may be a risk factor for adverse cardiovascular events. We would encourage replication of these findings in other cohorts, and are undertaking examination of this association in non-Caucasian individuals.

scholarly journals Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?

2021 ◽  
Author(s):  
Anna E. Bauer ◽  
Christy L. Avery ◽  
Min Shi ◽  
Clarice R. Weinberg ◽  
Andrew F. Olshan ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Maternal Smoking ◽  
Risk Allele ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Maternal Genotype ◽  
Family Based ◽  
Complex Relationships ◽  
Log Linear ◽  
Risk Of Preeclampsia

Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations. Study Design We conducted a nested case–control study within the Norwegian Mother, Father and Child Birth Cohort (1999–2008) of 2,596 mother–child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy. Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01). Conclusion Evidence for gene–smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene–environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures. Key Points

Fibrinogen Alpha and Gamma Genes and Factor VLeiden in Children with Thromboembolism: Results from Two Family-Based Association Studies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3816-3816
Author(s):  
Ulrike Nowak-Gottl ◽  
Hartmut Weiler ◽  
Sabine Thedieck ◽  
Tanja Seehafer ◽  
Monika Stoll
Keyword(s):  
Multiple Testing ◽  
Genetic Interaction ◽  
Association Studies ◽  
Large Family ◽  
Independent Study ◽  
Risk Haplotype ◽  
Nucleotide Polymorphisms ◽  
System A ◽  
Protective Haplotype ◽  
Family Based

Abstract Background: Fibrinogen, the precursor of fibrin, is an essential component of the hemostatic system. A previous large case-control study showed that genetic variation in the fibrinogen gamma gene (FGG) increased the risk for VT in adults. We investigated the association of haplotypes comprising the fibrinogen alpha (FGA) and gamma (FGG) genes, carriership of the Factor VLeiden-mutation and risk for VT in two large family-based study samples for pediatric thromboembolism. Methods: We genotyped 7 single nucleotide polymorphisms in FGA and FGG, and the G1691A Factor VLeiden polymorphism in 244 pediatric VT and 268 thrombo-embolic stroke families. Association was assessed using the Transmission Disequilibrium Test (TDT) and corrected for multiple testing. Results: Association analysis revealed that the FGA-H1 haplotype, and the FGG-H2 and -H3 haplotypes, were significantly associated with VT (FGA-H1, P=0.05; FGG: H2, P=0.032; H3, P=0.0216). In an independent study sample, FGA-H1 (P=0.0085) and FGG-H2 (P=0.05) were significantly associated with TS. When stratifying for FVLeiden carriership, the association between FGA and FGG and VT was more pronounced in FVLeiden-negative families (FGA-H1, P=0.0006; FGG-H2, P=0.0005). Homozygous carriership of the FGG-H2 risk haplotype resulted in the lowest fibrinogen γ′ content (γ′ levels: 22.7±13.7 vs. 26.8±12.0, P=0.013; % γ′: 7.63±3.05 vs. 9.46±3.17, P=2.3×10−5), with increasing concentrations of fibrinogen γ′ in heterozygote H2 carriers. Compound heterozygote carriers of one FGG-H2 risk and one FGG-H3 protective haplotype, showed significant increase in fibrinogen γ′ (P=0.000032), while fibrinogen levels remained unchanged. In contrast, homozygote carriers of the protective FGG-H3 haplotype showed the highest concentration of fibrinogen γ′ content (% γ′: 9.21±3.09, P=0.0031) with decreased total fibrinogen levels. Conclusion: Our results support an important role of genetic variants in FGA and FGG in thromboembolism in children and adults. Our data further suggest that the genetic architecture of VT is complex and involves subtle influences through susceptibility and protective haplotypes in FGG and a genetic interaction with the FVLeiden-mutation.

Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2336-2341 ◽  
Author(s):  
Ulrike Nowak-Göttl ◽  
Birgit Fröhlich ◽  
Sabine Thedieck ◽  
Andreas Huge ◽  
Monika Stoll
Keyword(s):  
Genetic Variation ◽  
Linkage Disequilibrium ◽  
Multiple Testing ◽  
Risk Haplotype ◽  
Nucleotide Polymorphisms ◽  
Permutation Testing ◽  
Protein Z ◽  
White Children ◽  
German Children ◽  
Family Based

Abstract To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)–based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, χ2 = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.

scholarly journals Covariate Adaptive Family-wise Error Rate Control for Genome-Wide Association Studies

Biometrika ◽  
2020 ◽  
Author(s):  
Huijuan Zhou ◽  
Xianyang Zhang ◽  
Jun Chen
Keyword(s):  
Error Rate ◽  
Rate Control ◽  
Multiple Testing ◽  
Statistical Power ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Family Wise Error Rate ◽  
Genome Wide

Abstract The family-wise error rate (FWER) has been widely used in genome-wide association studies. With the increasing availability of functional genomics data, it is possible to increase the detection power by leveraging these genomic functional annotations. Previous efforts to accommodate covariates in multiple testing focus on the false discovery rate control while covariate-adaptive FWER-controlling procedures remain under-developed. Here we propose a novel covariate-adaptive FWER-controlling procedure that incorporates external covariates which are potentially informative of either the statistical power or the prior null probability. An efficient algorithm is developed to implement the proposed method. We prove its asymptotic validity and obtain the rate of convergence through a perturbation-type argument. Our numerical studies show that the new procedure is more powerful than competing methods and maintains robustness across different settings. We apply the proposed approach to the UK Biobank data and analyze 27 traits with 9 million single-nucleotide polymorphisms tested for associations. Seventy-five genomic annotations are used as covariates. Our approach detects more genome-wide significant loci than other methods in 21 out of the 27 traits.

scholarly journals Comprehensive Genome-Wide Association Analysis Reveals the Genetic Basis of Root System Architecture in Soybean

2020 ◽  
Vol 11 ◽  
Author(s):  
Waldiodio Seck ◽  
Davoud Torkamaneh ◽  
François Belzile
Keyword(s):  
Root System ◽  
System Architecture ◽  
Phenotypic Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Primary Root ◽  
Root System Architecture ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

Increasing the understanding genetic basis of the variability in root system architecture (RSA) is essential to improve resource-use efficiency in agriculture systems and to develop climate-resilient crop cultivars. Roots being underground, their direct observation and detailed characterization are challenging. Here, were characterized twelve RSA-related traits in a panel of 137 early maturing soybean lines (Canadian soybean core collection) using rhizoboxes and two-dimensional imaging. Significant phenotypic variation (P &lt; 0.001) was observed among these lines for different RSA-related traits. This panel was genotyped with 2.18 million genome-wide single-nucleotide polymorphisms (SNPs) using a combination of genotyping-by-sequencing and whole-genome sequencing. A total of 10 quantitative trait locus (QTL) regions were detected for root total length and primary root diameter through a comprehensive genome-wide association study. These QTL regions explained from 15 to 25% of the phenotypic variation and contained two putative candidate genes with homology to genes previously reported to play a role in RSA in other species. These genes can serve to accelerate future efforts aimed to dissect genetic architecture of RSA and breed more resilient varieties.

EpiPen: An R Package to Investigate Two-Locus Epistatic Models

2014 ◽  
Vol 17 (4) ◽  
Author(s):  
Raymond K. Walters ◽  
Charles Laurin ◽  
Gitta H. Lubke
Keyword(s):  
Power Analysis ◽  
R Package ◽  
Simulation Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Epistatic Interactions ◽  
Model Interpretation ◽  
Genome Wide ◽  
Using Data ◽  
Power Analyses

Epistasis is a growing area of research in genome-wide studies, but the differences between alternative definitions of epistasis remain a source of confusion for many researchers. One problem is that models for epistasis are presented in a number of formats, some of which have difficult-to-interpret parameters. In addition, the relation between the different models is rarely explained. Existing software for testing epistatic interactions between single-nucleotide polymorphisms (SNPs) does not provide the flexibility to compare the available model parameterizations. For that reason we have developed an R package for investigating epistatic and penetrance models, EpiPen, to aid users who wish to easily compare, interpret, and utilize models for two-locus epistatic interactions. EpiPen facilitates research on SNP-SNP interactions by allowing the R user to easily convert between common parametric forms for two-locus interactions, generate data for simulation studies, and perform power analyses for the selected model with a continuous or dichotomous phenotype. The usefulness of the package for model interpretation and power analysis is illustrated using data on rheumatoid arthritis.

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