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A transcription-centric model of SNP-age interaction.

ABSTRACT: Complex age-associated phenotypes are caused, in part, by an interaction between an individual's genotype and age. The mechanisms governing such interactions are however not entirely understood. Here, we provide a novel transcriptional mechanism-based framework-SNiPage, to investigate such interactions, whereby a transcription factor (TF) whose expression changes with age (age-associated TF), binds to a polymorphic regulatory element in an allele-dependent fashion, rendering the target gene's expression dependent on both, the age and the genotype. Applying SNiPage to GTEx, we detected ~637 significant TF-SNP-Gene triplets on average across 25 tissues, where the TF binds to a regulatory SNP in the gene's promoter or putative enhancer and potentially regulates its expression in an age- and allele-dependent fashion. The detected SNPs are enriched for epigenomic marks indicative of regulatory activity, exhibit allele-specific chromatin accessibility, and spatial proximity to their putative gene targets. Furthermore, the TF-SNP interaction-dependent target genes have established links to aging and to age-associated diseases. In six hypertension-implicated tissues, detected interactions significantly inform hypertension state of an individual. Lastly, the age-interacting SNPs exhibit a greater proximity to the reported phenotype/diseases-associated SNPs than eSNPs identified in an interaction-independent fashion. Overall, we present a novel mechanism-based model, and a novel framework SNiPage, to identify functionally relevant SNP-age interactions in transcriptional control and illustrate their potential utility in understanding complex age-associated phenotypes.

SUBMITTER: Wang K

PROVIDER: S-EPMC7997000 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The capability of correlating specific genotypes with human diseases is a complex issue in spite of all advantages arisen from high-throughput technologies, such as Genome Wide Association Studies (GWAS). New tools for genetic variants interpretation and for Single Nucleotide Polymorphisms (SNPs) prioritization are actually needed. Given a list of the most relevant SNPs statistically associated to a specific pathology as result of a genotype study, a critical issue is the identification of genes that are effectively related to the disease by re-scoring the importance of the identified genetic variations. Vice versa, given a list of genes, it can be of great importance to predict which SNPs can be involved in the onset of a particular disease, in order to focus the research on their effects.We propose a new bioinformatics approach to support biological data mining in the analysis and interpretation of SNPs associated to pathologies. This system can be employed to design custom genotyping chips for disease-oriented studies and to re-score GWAS results. The proposed method relies (1) on the data integration of public resources using a gene-centric database design, (2) on the evaluation of a set of static biomolecular annotations, defined as features, and (3) on the SNP scoring function, which computes SNP scores using parameters and weights set by users. We employed a machine learning classifier to set default feature weights and an ontological annotation layer to enable the enrichment of the input gene set. We implemented our method as a web tool called SNPranker 2.0 (http://www.itb.cnr.it/snpranker), improving our first published release of this system. A user-friendly interface allows the input of a list of genes, SNPs or a biological process, and to customize the features set with relative weights. As result, SNPranker 2.0 returns a list of SNPs, localized within input and ontologically enriched genes, combined with their prioritization scores.Different databases and resources are already available for SNPs annotation, but they do not prioritize or re-score SNPs relying on a-priori biomolecular knowledge. SNPranker 2.0 attempts to fill this gap through a user-friendly integrated web resource. End users, such as researchers in medical genetics and epidemiology, may find in SNPranker 2.0 a new tool for data mining and interpretation able to support SNPs analysis. Possible scenarios are GWAS data re-scoring, SNPs selection for custom genotyping arrays and SNPs/diseases association studies.

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A transcription-centric model of SNP-age interaction.

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