GWAS3D: detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications

Abstract

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.

Interrogation of allelic chromatin states in human cells by high-density ChIP-genotyping

“…6,7 Studies utilizing this and other similar data sets have highlighted the role of open chromatin regions, histone modifications and transcription factor binding sites in regulating gene expression and/or disease risk, with variants in these regions frequently enriched for eQTLs and/or GWAS SNPs. 1,[8][9][10] Open chromatin regions have previously been studied using DNase I, an enzyme which selectively cuts at nucleosomedepleted areas of the genome. 11 More recently, the DNase I protocol has been combined with next generation sequencing, in a procedure known as DNase-seq, to generate genome-wide maps of DNase I Hypersensitive Sites (DHSs).…”

Maternal Nutrition and Epigenetic Perturbation: Modeling Trends to Translation

“…The development of new computational tools to analyze complex data and correlative relationships is required particularly in the area of epigenetic effects where statistical analysis still poses an especially difficult task. Of equal importance, computational tools and theoretical models are being developed to account for epigenetic variation in genetic association studies [63,64]. Hopefully, this will increase power to identify previously inaccessible heritable disease markers.…”

Identifying the Risky SNP of Osteoporosis with ID3-PEP Decision Tree Algorithm

“…Combining with GO and pathway analysis, we found that the hub proteins associated and the Wnt signaling pathway were related to the mesenchymal stem cell differentiation and hormone signaling that was related to the metabolism of osteoporosis [9]. Finally, it was found that the osteoporosis GWAS-associated SNPs in special region of genes had longrange interaction signal with other locus by analyzing the long-range interaction of osteoporosis associated SNPs on GWAS3D [10].…”