Submitted to: Biomed Central (BMC) Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 13, 2011
Publication Date: October 13, 2011
Citation: Richardson, K., Lai, C., Parnell, L.D., Lee, Y., Ordovas, J. 2011. A genome-wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS. Biomed Central (BMC) Genomics. 2:504. Interpretive Summary: In this study we have surveyed human Single-Nucleotide Polymorphisms (SNPs are DNA sequence variations) data and identified variants that provide functional hypotheses for observed genomewide association studies’ (GWAS) associations. Genomewide association studies (GWAS) have identified hundreds of common human genetic variants correlated with a significant change in disease related traits. However, there have been few hypotheses put forth, and fewer tested, to explain the biological mechanism through which the genetic variant may be modulating these traits. We have performed a genome-wide survey of 1000 Genomes Project genetic variation data for variants predicted to induce allele-specific miR-mRNA interactions. Further, we identify 92 of these variants as previously listed in genomewide association studies (GWAS), or strongly correlated with genomewide association studies’ (GWAS) SNPs. We survey other publically available data and demonstrate four of these 92 SNPs have supporting co-expression and eQTL evidence, suggesting these variants as likely functional candidates. These findings are of interest to the health care professionals because they demonstrate how publicly available resources can be used to identify high priority candidate SNPs for functional studies relevant to disease prevention.
Technical Abstract: Gene variants within regulatory regions are thought to be major contributors of the variation of complex traits/diseases. Genome wide association studies (GWAS), have identified scores of genetic variants that appear to contribute to human disease risk. However, most of these variants do not appear to be functional. In the present study, focused on functional variants related with the binding of microRNAs (miR), we utilized SNP data, including newly released 1000 Genomes Project data to perform a genome-wide scan of SNPs that abrogate or create miR recognition element (MRE) seed sites (MRESS). We identified 2723 SNPs disrupting, and 22295 SNPs creating MRESSs. We estimated the percent of SNPs falling within both validated (5%) and predicted conserved MRESSs (3%). We determined 87 of these MRESS SNPs were listed in GWAS association studies, or in strong LD with a GWAS SNP, and may represent the functional variants of identified GWAS SNPs. Furthermore, 39 of these have evidence of co-expression of target mRNA and the predicted miR. We also gathered previously published eQTL data supporting a functional role for four of these SNPs shown to associate with disease phenotypes. Comparison of FST statistics (a measure of population subdivision) for predicted MRESS SNPs against non MRESS SNPs revealed a significantly higher (P = 0.0004) degree of subdivision among MRESS SNPs, suggesting a role for these SNPs in environmentally driven selection. We have demonstrated the potential of publicly available resources to identify high priority candidate SNPs for functional studies and for disease risk prediction.