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Open Access Highly Accessed Research article

On the identification of potential regulatory variants within genome wide association candidate SNP sets

Chih-yu Chen12, I-Shou Chang3, Chao A Hsiung4 and Wyeth W Wasserman15*

Author Affiliations

1 Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada

2 Graduate Program in Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada

3 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan

4 Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan

5 Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

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BMC Medical Genomics 2014, 7:34  doi:10.1186/1755-8794-7-34

Published: 11 June 2014

Abstract

Background

Genome wide association studies (GWAS) are a population-scale approach to the identification of segments of the genome in which genetic variations may contribute to disease risk. Current methods focus on the discovery of single nucleotide polymorphisms (SNPs) associated with disease traits. As there are many SNPs within identified risk loci, and the majority of these are situated within non-coding regions, a key challenge is to identify and prioritize variants affecting regulatory sequences that are likely to contribute to the phenotype assessed.

Methods

We focused investigation on SNPs within lung and breast cancer GWAS loci that reached genome-wide significance for potential roles in gene regulation with a specific focus on SNPs likely to disrupt transcription factor binding sites. Within risk loci, the regulatory potential of sub-regions was classified using relevant open chromatin and epigenetic high throughput sequencing data sets from the ENCODE project in available cancer and normal cell lines. Furthermore, transcription factor affinity altering variants were predicted by comparison of position weight matrix scores between disease and reference alleles. Lastly, ChIP-seq data of transcription associated factors and topological domains were included as binding evidence and potential gene target inference.

Results

The sets of SNPs, including both the disease-associated markers and those in high linkage disequilibrium with them, were significantly over-represented in regulatory sequences of cancer and/or normal cells; however, over-representation was generally not restricted to disease-relevant tissue specific regions. The calculated regulatory potential, allelic binding affinity scores and ChIP-seq binding evidence were the three criteria used to prioritize candidates. Fitting all three criteria, we highlighted breast cancer susceptibility SNPs and a borderline lung cancer relevant SNP located in cancer-specific enhancers overlapping multiple distinct transcription associated factor ChIP-seq binding sites.

Conclusion

Incorporating high throughput sequencing epigenetic and transcription factor data sets from both cancer and normal cells into cancer genetic studies reveals potential functional SNPs and informs subsequent characterization efforts.

Keywords:
GWAS; Lung cancer; Regulatory regions; Gene regulation; Transcription factor binding site alteration; Enhancer; Topological domains