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VannoPortal: multiscale functional annotation of human genetic variants for interrogating molecular mechanism of traits and diseases.

ABSTRACT: Interpreting the molecular mechanism of genomic variations and their causal relationship with diseases/traits are important and challenging problems in the human genetic study. To provide comprehensive and context-specific variant annotations for biologists and clinicians, here, by systematically integrating over 4TB genomic/epigenomic profiles and frequently-used annotation databases from various biological domains, we develop a variant annotation database, called VannoPortal. In general, the database has following major features: (i) systematically integrates 40 genome-wide variant annotations and prediction scores regarding allele frequency, linkage disequilibrium, evolutionary signature, disease/trait association, tissue/cell type-specific epigenome, base-wise functional prediction, allelic imbalance and pathogenicity; (ii) equips with our recent novel index system and parallel random-sweep searching algorithms for efficient management of backend databases and information extraction; (iii) greatly expands context-dependent variant annotation to incorporate large-scale epigenomic maps and regulatory profiles (such as EpiMap) across over 33 tissue/cell types; (iv) compiles many genome-scale base-wise prediction scores for regulatory/pathogenic variant classification beyond protein-coding region; (v) enables fast retrieval and direct comparison of functional evidence among linked variants using highly interactive web panel in addition to plain table; (vi) introduces many visualization functions for more efficient identification and interpretation of functional variants in single web page. VannoPortal is freely available at http://mulinlab.org/vportal.

SUBMITTER: Huang D

PROVIDER: S-EPMC8728305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Over the past decade, hundreds of genome-wide association studies (GWAS) have implicated genetic variants in various diseases, including cancer. However, only a few of these variants have been functionally characterized to date, mainly because the majority of the variants reside in non-coding regions of the human genome with unknown function. A comprehensive functional annotation of the candidate variants is thus necessary to fill the gap between the correlative findings of GWAS and the development of therapeutic strategies. By integrating large-scale multi-omics datasets such as the Cancer Genome Atlas (TCGA) and the Encyclopedia of DNA Elements (ENCODE), we performed multivariate linear regression analysis of expression quantitative trait loci, sequence permutation test of transcription factor binding perturbation, and modeling of three-dimensional chromatin interactions to analyze the potential molecular functions of 2,813 single nucleotide variants in 93 genomic loci associated with estrogen receptor-positive breast cancer. To facilitate rapid progress in functional genomics of breast cancer, we have created "Analysis of Breast Cancer GWAS" (ABC-GWAS), an interactive database of functional annotation of estrogen receptor-positive breast cancer GWAS variants. Our resource includes expression quantitative trait loci, long-range chromatin interaction predictions, and transcription factor binding motif analyses to prioritize putative target genes, causal variants, and transcription factors. An embedded genome browser also facilitates convenient visualization of the GWAS loci in genomic and epigenomic context. ABC-GWAS provides an interactive visual summary of comprehensive functional characterization of estrogen receptor-positive breast cancer variants. The web resource will be useful to both computational and experimental biologists who wish to generate and test their hypotheses regarding the genetic susceptibility, etiology, and carcinogenesis of breast cancer. ABC-GWAS can also be used as a user-friendly educational resource for teaching functional genomics. ABC-GWAS is available at http://education.knoweng.org/abc-gwas/.

Dataset Information

VannoPortal: multiscale functional annotation of human genetic variants for interrogating molecular mechanism of traits and diseases.

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