scholarly journals Prostate cancer risk SNP rs10993994 is a trans-eQTL for SNHG11 mediated through MSMB

2020 ◽  
Vol 29 (10) ◽  
pp. 1581-1591 ◽  
Author(s):  
Mesude Bicak ◽  
Xing Wang ◽  
Xiaoni Gao ◽  
Xing Xu ◽  
Riina-Minna Väänänen ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Prostate Cancer Risk ◽  
Fold Increase ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Normal Prostate ◽  
Cis Acting ◽  
Genome Wide ◽  
Trait Locus

Abstract How genome-wide association studies-identified single-nucleotide polymorphisms (SNPs) affect remote genes remains unknown. Expression quantitative trait locus (eQTL) association meta-analysis on 496 prostate tumor and 602 normal prostate samples with 117 SNPs revealed novel cis-eQTLs and trans-eQTLs. Mediation testing and colocalization analysis demonstrate that MSMB is a cis-acting mediator for SNHG11 (P < 0.01). Removing rs10993994 in LNCaP cell lines by CRISPR/Cas9 editing shows that the C-allele corresponds with an over 100-fold increase in MSMB expression and 5-fold increase in SNHG11 compared with the T-allele. Colocalization analysis confirmed that the same set of SNPs associated with MSMB expression is associated with SNHG11 expression (posterior probability of shared variants is 66.6% in tumor and 91.4% in benign). These analyses further demonstrate variants driving MSMB expression differ in tumor and normal, suggesting regulatory network rewiring during tumorigenesis.

scholarly journals Association of CNVs with methylation variation

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Xinghua Shi ◽  
Saranya Radhakrishnan ◽  
Jia Wen ◽  
Jin Yun Chen ◽  
Junjie Chen ◽  
...  
Keyword(s):  
Association Studies ◽  
Copy Number Variants ◽  
Cpg Methylation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Cellular Phenotype ◽  
Genome Wide ◽  
A Genome ◽  
Physical Interactions ◽  
Trait Locus

Abstract Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

scholarly journals Meta-Analysis of Allergy Genome-Wide Association Studies

2020 ◽  
Author(s):  
Ronin Sharma
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Significance Level ◽  
Genome Wide ◽  
Linear Regressions

AbstractAllergies are complex conditions involving both environmental and genetic factors. The genetic basis underlying allergic disease is investigated through genetic association studies. Genome-wide association studies (GWAS) leverage sequenced data to identify genetic mutations, such as single-nucleotide polymorphisms (SNPs), associated with phenotypes of interest. Machine learning can be used to analyze large datasets and generate predictive models. In this study, several classification models were created to predict the significance level of SNPs associated with allergies. Summary statistics were obtained from the GWAS Catalog and combined from several studies. Biological features such as chromosomal location, base pair location, effect allele, and odds ratio were used to train the models. The models ranged from simple linear regressions to multi-layer neural networks. The final models reached accuracies of 80% and reflect the features that have the largest impact on a SNP’s association level.

scholarly journals Variation rs9929218 and Risk of the Colorectal Cancer and Adenomas: A Meta-analysis

2020 ◽  
Author(s):  
Huiyan Wang ◽  
Dongying Gu ◽  
Miao Yu ◽  
Yanjun Hu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Colorectal ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Accurate Approximation ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Different Populations

Abstract Backgrounds: Genome-wide association studies (GWAS) have identified multiple common CRC-related (colorectal cancer) SNPs (single nucleotide polymorphisms) including the Cadherin 1(CDH1) rs9929218 may act by increasing the risk of colorectal cancer, colorectal adenoma, or both. These studies, however, reported inconsistent associations. Methods: To derive a more accurate approximation of the connection, we carried out a meta-analysis of 12 published pieces of research including 11,590 controls and 8,192 cases. We used odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations' strength.Results: Meta-analysis implied considerable association between CRC and rs9929218 (OR = 1.21, 95%CI 1.04-1.42 for GG versus AA; OR = 1.22, 95%CI 1.05-1.42 for GG/AG versus AA).In the subgroup analyses, significantly increased risks were found among Europeans.Conclusions: In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans.

NINJ2 Gene Polymorphisms and Susceptibility to Ischemic Stroke: An Updated Meta-Analysis

2019 ◽  
Vol 16 (3) ◽  
pp. 273-287
Author(s):  
Fangfang Nie ◽  
Mingli Yu ◽  
Mengwei Liu ◽  
Mengke Shang ◽  
Fanxin Zeng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Gene Polymorphisms ◽  
Association Studies ◽  
Meta Analysis ◽  
Health Condition ◽  
Genetic Models ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Significant Disease

Background: Ischemic stroke (IS) is a significant disease which threatens human health condition. Genome-wide association studies (GWAS) have demonstrated that two intergenic single- nucleotide polymorphisms (SNPs) rs11833579 and rs12425791 G>A on chromosome 12p13 are associated with IS susceptibility. However, later studies came to contradictory outcomes. Thus, we carried out a meta-analysis to identify the association between nerve injury-induced protein 2 (NINJ2) gene polymorphisms (rs11833579 and rs12425791) and the risk of IS. Methods: PubMed, Embase, Web of Science, CBM, Wanfang, VIP, and CNKI databases were searched until March 2019. Data was analyzed by RevMan 5.3 and STATA 12.0 software. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Results: Eighteen qualified articles were selected in total. For rs12425791 and rs11833579, a total of 14055 cases with 13148 controls and 10635 cases with 10462 controls, respectively, were identified for the present study. Our meta-analysis found that rs12425791 was associated with IS for three genetic models (allele model: OR=1.04, 95% CI: 1.00-1.08, P=0.04; dominant model: OR=1.06, 95% CI: 1.01-1.12, P=0.01 and heterozygous model: OR=1.07, 95% CI: 1.01-1.12, P=0.02). Whereas rs11833579 polymorphism was not associated with IS among different genetic models. Conclusion: NINJ2 gene rs12425791 confers a susceptible factor for IS, while there is no association between NINJ2 gene rs11833579 and IS. Larger sample size studies should be performed to find the association between NINJ2 gene and IS.

Genetically proxied morning chronotype was associated with a reduced risk of prostate cancer

SLEEP ◽  
2021 ◽  
Author(s):  
Xiaohui Sun ◽  
Ding Ye ◽  
Mengting Jiang ◽  
Yu Qian ◽  
Yingying Mao
Keyword(s):  
Prostate Cancer ◽  
Causal Effect ◽  
Association Studies ◽  
Meta Analysis ◽  
Prostate Cancer Risk ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Primary Analysis ◽  
Weighted Median ◽  
Reduced Risk

Abstract Study Objectives Observational epidemiological studies have suggested that chronotype may play a role in the pathogenesis and progression of prostate cancer. However, whether there is a causal association remains unknown. The aim of the present study was to examine the potential causal relationship between chronotype and prostate cancer risk using a Mendelian randomization (MR) design. Methods A total of 268 single nucleotide polymorphisms associated with chronotype were selected from a meta-analysis of genome-wide association studies of 697,828 individuals. The genetic association data for prostate cancer was derived from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) Consortium (79,148 cases and 61,106 controls). Inverse-variance-weighted (IVW) method was used as the primary analysis to calculate the causal effect estimates. The weighted-median method, MR-Egger regression, MR-PRESSO test, and multivariable MR analyses were applied as sensitivity analysis. Results Genetically predicted morningness (scaled to a sleep midpoint of 1 hour earlier) had a reduced risk of prostate cancer, with an odds ratio of 0.71 (95% confidence interval (CI): 0.54-0.94 by IVW), compared with the eveningness. Similar causal effect estimates were also observed by using the weighted median and MR-PRESSO analyses. In addition, results from the multivariable MR analysis supported the findings from the univariable MR analyses. No indication of horizontal pleiotropy was observed in the MR-Egger analysis (P for intercept =0.234). Conclusion Our findings provide evidence of a causal protective effect of morning chronotype on the risk of prostate cancer.

scholarly journals Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD

2014 ◽  
Vol 45 (1) ◽  
pp. 60-75 ◽  
Author(s):  
Akkelies E. Dijkstra ◽  
H. Marike Boezen ◽  
Maarten van den Berge ◽  
Judith M. Vonk ◽  
Pieter S. Hiemstra ◽  
...  
Keyword(s):  
Genetic Model ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Chronic Obstructive ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Mucus Hypersecretion ◽  
Genome Wide

Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD.We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (≥20 pack-years) with COPD (n=849, 39.9% CMH) and without COPD (n=1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs.Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p=5.43×10−5) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p=0.007). In non-COPD subjects, four SNPs had a p-value <10−5 in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p=7.57×10−6, OR 1.48) and with significantly increased MAML3 expression in lung tissue (p=2.59×10−12).Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.

scholarly journals Variation rs9929218 and risk of the colorectal Cancer and adenomas: A meta-analysis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huiyan Wang ◽  
Dongying Gu ◽  
Miao Yu ◽  
Yanjun Hu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Colorectal ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Accurate Approximation ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Different Populations

Abstract Backgrounds Genome-wide association studies (GWAS) have identified multiple common CRC-related (colorectal cancer) SNPs (single nucleotide polymorphisms) including the Cadherin 1(CDH1) rs9929218 may act by increasing the risk of colorectal cancer, colorectal adenoma, or both. These studies, however, reported inconsistent associations. Methods To derive a more accurate approximation of the connection, we carried out a meta-analysis of 12 published pieces of research including 11,590 controls and 8192 cases. We used odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations’ strength. Results Meta-analysis implied considerable association between CRC and rs9929218 (OR = 1.21, 95%CI 1.04–1.42 for GG versus AA; OR = 1.22, 95%CI 1.05–1.42 for GG/AG versus AA). In the subgroup analyses, significantly increased risks were found among Europeans. Conclusions In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans.

scholarly journals A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

2019 ◽  
Vol 28 (19) ◽  
pp. 3327-3338 ◽  
Author(s):  
Jonathan P Bradfield ◽  
Suzanne Vogelezang ◽  
Janine F Felix ◽  
Alessandra Chesi ◽  
Øyvind Helgeland ◽  
...  
Keyword(s):  
Childhood Obesity ◽  
Late Onset ◽  
Association Studies ◽  
Meta Analysis ◽  
Causal Variant ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
South American ◽  
Nucleotide Polymorphisms ◽  
Genome Wide

Abstract Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently &lt;50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

scholarly journals Genetic Susceptibility to Clozapine-Induced Agranulocytosis/Neutropenia Across Ethnicities: Results From a New Cohort of Turkish and Other Caucasian Participants, and Meta-Analysis

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Cynthia Okhuijsen-Pfeifer ◽  
Yavuz Ayhan ◽  
Bochao D Lin ◽  
Kristel R van Eijk ◽  
Erwin Bekema ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Clinical Decision Making ◽  
Association Studies ◽  
Meta Analysis ◽  
Turkish Population ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Total Group ◽  
Genome Wide ◽  
North Western

Abstract Clozapine (CLZ) is considered the most effective antipsychotic, but its use is associated with neutropenia (CIN) and agranulocytosis (CIA). Although the exact etiology of these hazardous side effects is unknown, 4 genetic polymorphisms have been implicated by genome-wide association studies (GWAS), mostly performed in North-Western Europeans. These polymorphisms are rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs1546308/rs149104283 (SLCO1B3/7), several of which were not directly genotyped but imputed. To test whether these 4 single-nucleotide polymorphisms (SNPs) are associated with CIN/CIA in a Turkish population and in a more extensive group of Caucasians, we directly genotyped these polymorphisms using Taqman and Sanger sequencing and performed logistic regression. We divided our participants (234 CLZ-using participants of whom 31 CIN/CIA cases) into (1) North-Western European, (2) Turkish, (3) Caucasian (=1 + 2); and (4) a total group (Caucasian + other ethnicities). Rs113332494 (HLA-DQB1) was significantly associated with CIN/CIA in the total group (P = 3.5 × 10−8), in the Caucasian group (P = 9.3 × 10−6) and in the Turkish group (P = 2.8 × 10−5). Rs41549217 (HLA-B) was nominally significant in the Caucasian group (P = .018). In meta-analysis of our results and the previously reported genome-wide results, 3 SNPs were significantly associated with CIN/CIA in participants with Caucasian ancestry: rs113332494 (P = 2.05 × 10−8), rs41549217 (P = 7.19 × 10−9), and rs149104283 (P = 5.54 × 10−9), with the result for rs1546308 (SCLO1B3/SCLO1B7) being significantly heterogeneous across studies. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop CIN/CIA. Pharmacogenetic testing can complement clinical decision making and thus empower appropriate CLZ prescribing, but ancestry should be taken into account when performing such testing for CLZ.

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