GWAS3D: Detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications.
- Authors
- Li, Mulin Jun; Wang, Lily Yan; Xia, Zhengyuan; Sham, Pak Chung; Wang, Junwen
- Year
- 2013
- Journal
- Nucleic acids research
- PMID
- 23723249
- DOI
- 10.1093/nar/gkt456
- PMCID
- PMC3692118
Interpreting the genetic variants located in the regulatory regions, such as enhancers and promoters, is an indispensable step to understand molecular mechanism of complex traits. Recent studies show that genetic variants detected by genome-wide association study (GWAS) are significantly enriched in the regulatory regions. Therefore, detecting, annotating and prioritizing of genetic variants affecting gene regulation are critical to our understanding of genotype-phenotype relationships. Here, we developed a web server GWAS3D to systematically analyze the genetic variants that could affect regulatory elements, by integrating annotations from cell type-specific chromatin states, epigenetic modifications, sequence motifs and cross-species conservation. The regulatory elements are inferred from the genome-wide chromosome interaction data, chromatin marks in 16 different cell types and 73 regulatory factors motifs from the Encyclopedia of DNA Element project. Furthermore, we used these function elements, as well as risk haplotype, binding affinity, conservation and P-values reported from the original GWAS to reprioritize the genetic variants. Using studies from low-density lipoprotein cholesterol, we demonstrated that our reprioritizing approach was effective and cell type specific. In conclusion, GWAS3D provides a comprehensive annotation and visualization tool to help users interpreting their results. The web server is freely available at http://jjwanglab.org/gwas3d.
The workflow of GWAS3D (see the description of pipeline for details).
The circle plot of GWAS3D for all GWAS SNPs of diabetes mellitus from NHGRI GWAS Catalog based on the K562 cell line and CEU population. Significant GWAS3D results are presented by the circle plot. From the outer to inner, there are significant regulatory variants and distal interaction regions, genes and genomic loci, chromosome number and distal interaction indicators. For example, GWAS SNP rs805305 is detected as a significant regulatory variant by GWAS3D (a), this variant located on the intronic region of DDAH2 (b) in chromosome 6 (c). One of the important regulatory features for this variant, which can be viewed from this plot, is that the region has a long-range interaction signal to another locus near VWA7 (d), interactive elements with significant regulatory variant will start with ‘I_’). The red line indicated this signal (e), and the intensity of interaction is represented by width.
The ‘GWAS3D INFO’ page for detailed information of regulatory variant. The web page consists of two parts: (a) tabular viewer for significant variant detected by GWAS3D. (b) six annotation tabs of GWAS3D.
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