scholarly journals Assessment of possible association between rs378854 and prostate cancer risk in the Serbian population

2013 ◽  
Vol 65 (2) ◽  
pp. 475-486
Author(s):  
G. Brajuskovic ◽  
Zorana Nikolic ◽  
A. Kojic ◽  
Dusanka Savic-Pavicevic ◽  
Snezana Cerovic ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Quality Analysis ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Study Population ◽  
Hardy Weinberg Equilibrium

Prostate cancer (PCa) is the second most commonly diagnosed cancer among men worldwide. Despite its high incidence rate, the molecular basis of PCa onset and its progression remains little understood. Genome-wide association studies (GWAS) have greatly contributed to the identification of single nucleotide polymorphisms (SNP) associated with PCa risk. Several GWAS identified 8q24 as one of the most significant PCa-associated regions. The aim of this study was to evaluate the association of SNP rs378854 at 8q24 with PCa risk in the Serbian population. The study population included 261 individuals diagnosed with PCa, 257 individuals diagnosed with benign prostatic hyperplasia (BPH) and 106 healthy controls. Data quality analysis yielded results showing deviations from Hardy-Weinberg equilibrium in groups of PCa patients and BPH patients as well as in the control group. There was no significant association between alleles and genotypes of the genetic variant rs378854 and PCa risk in the Serbian population.

scholarly journals Physical activity and risk of Alzheimer disease

Neurology ◽  
2020 ◽  
Vol 95 (13) ◽  
pp. e1897-e1905
Author(s):  
Sebastian E. Baumeister ◽  
André Karch ◽  
Martin Bahls ◽  
Alexander Teumer ◽  
Michael F. Leitzmann ◽  
...  
Keyword(s):  
Physical Activity ◽  
Alzheimer Disease ◽  
Association Studies ◽  
Vigorous Physical Activity ◽  
Primary Study ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Study Population

ObjectiveEvidence from observational studies for the effect of physical activity on the risk of Alzheimer disease (AD) is inconclusive. We performed a 2-sample mendelian randomization analysis to examine whether physical activity is protective for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were used. The primary study population included 21,982 patients with AD and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNPs) known at p < 5 × 10−8 to be associated with average accelerations and 8 SNPs associated at p < 5 × 10−7 with vigorous physical activity (fraction of accelerations >425 milligravities) served as instrumental variables.ResultsThere was no association between genetically predicted average accelerations with the risk of AD (inverse variance weighted odds ratio [OR] per SD increment: 1.03, 95% confidence interval 0.97–1.10, p = 0.332). Genetic liability for fraction of accelerations >425 milligravities was unrelated to AD risk.ConclusionThe present study does not support a causal association between physical activity and risk of AD.

scholarly journals Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

2021 ◽  
Author(s):  
Sylvan C Baca ◽  
Cassandra Singler ◽  
Soumya Zacharia ◽  
Ji-Heui Seo ◽  
Tunc Morova ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Binding Sites ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Context Dependent

Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

scholarly journals Post genome-wide association studies functional characterization of prostate cancer risk loci

BMC Genomics ◽  
2013 ◽  
Vol 14 (Suppl 8) ◽  
pp. S9 ◽  
Author(s):  
Junfeng Jiang ◽  
Weirong Cui ◽  
Wanwipa Vongsangnak ◽  
Guang Hu ◽  
Bairong Shen
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Association Studies ◽  
Functional Characterization ◽  
Prostate Cancer Risk ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

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 Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

2021 ◽  
Author(s):  
Matthew Freedman ◽  
Sylvan Baca ◽  
Cassandra Singler ◽  
Soumya Zacharia ◽  
Ji-Heui Seo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Steady State ◽  
Binding Sites ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Context Dependent

Abstract Methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs), are widely used to functionally annotate trait-associated variants, but they are limited in identifying context-dependent effects on transcription. To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for nominating variants that impact traits through their effects on chromatin state. CWAS associates the genetic determinants of cistromes (e.g., the genome-wide profiles of transcription factor binding sites or histone modifications) with traits using summary statistics from genome-wide association studies (GWAS). We performed CWASs of prostate cancer and androgen-related traits, using a reference panel of 307 prostate cistromes from 165 individuals. CWAS nominated susceptibility regulatory elements or androgen receptor (AR) binding sites at 52 out of 98 known prostate cancer GWAS loci and implicated an additional 17 novel loci. We functionally validated a subset of our results using CRISPRi and in vitro reporter assays. At 28 of the 52 risk loci, CWAS identified regulatory mechanisms that are not observable via eQTLs, implicating genes with complex or context-specific regulation that are overlooked by current approaches that relying on steady-state transcript measurements. CWAS genes include transcription factors that govern prostate development such as NKX3-1, HOXB13, GATA2, and KLF5. Moreover, CWAS boosts discovery power in modestly sized GWAS, identifying novel genetic associations mediated through AR binding for androgen-related phenotypes, including resistance to prostate cancer therapy. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting context-dependent transcriptional regulation.

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 &lt; 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.

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