Dataset Information

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

ABSTRACT:

Background

Over the last decade, genome-wide association studies (GWAS) have discovered many risk associated single nucleotide polymorphisms (SNPs) of prostate cancer (PCa). However, the majority of the associated PCa SNPs, including those in linkage disequilibrium (LD) blocks, are generally not located in protein coding regions. The systematical investigation of the functional roles of these SNPs, especially the non-coding SNPs, becomes very necessary and helpful to the understanding of the molecular mechanism of PCa.

Results

In this work, we proposed a comprehensive framework at network level to integrate the SNP annotation, target gene assignment, gene ontology (GO) classification, pathway enrichment analysis and regulatory network reconstruction to illustrate the molecular functions of PCa associated SNPs. By LD expansion, we first identified 1828 LD SNPs using 49 reported GWAS SNPs as a start. We carefully annotated these 1828 LD SNPs via either UCSC known genes, UCSC regulation elements, or expression Quantitative Trait Loci (eQTL) data. As a result, we found 1154 SNPs were functionally annotated and obtained 205 unique PCa genes for further enrichment analysis. The enriched GO biological processes and pathways were found mainly related to regulation of cell death, apoptosis, cell proliferation, and metabolic process, which have been proved essential to cancer development. We constructed PCa genes specific transcription regulatory networks, finding several important genetic regulators for PCa, such as IGF-1/IGF-2 receptors, SP1, CREB1, and androgen receptor (AR).

Conclusions

A comprehensive framework was proposed for integrative and systematic analysis of PCa SNPs, the analysis can provide essential information for the understanding of the regulatory function of GWAS SNPs in PCa, and will facilitate the discovery of novel candidate biomarkers for diagnosis and prognosis of PCa.

SUBMITTER: Jiang J

PROVIDER: S-EPMC4042239 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

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

Jiang Junfeng J Cui Weirong W Vongsangnak Wanwipa W Hu Guang G Shen Bairong B

BMC genomics 20131209

<h4>Background</h4>Over the last decade, genome-wide association studies (GWAS) have discovered many risk associated single nucleotide polymorphisms (SNPs) of prostate cancer (PCa). However, the majority of the associated PCa SNPs, including those in linkage disequilibrium (LD) blocks, are generally not located in protein coding regions. The systematical investigation of the functional roles of these SNPs, especially the non-coding SNPs, becomes very necessary and helpful to the understanding of ...[more]

PMID: 24564736

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Project description:BackgroundAlzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74 046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry.Recent developmentsThree new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94 437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388 324 and 534 403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research. WHERE NEXT?: The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.

Dataset Information

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

Background

Results

Conclusions

Publications

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

Similar Datasets

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