Cis-acting polymorphisms affect complex traits through modifications of microRNA regulation pathways.

ABSTRACT: Genome-wide association studies (GWAS) have become an effective tool to map genes and regions contributing to multifactorial human diseases and traits. A comparably small number of variants identified by GWAS are known to have a direct effect on protein structure whereas the majority of variants is thought to exert their moderate influences on the phenotype through regulatory changes in mRNA expression. MicroRNAs (miRNAs) have been identified as powerful posttranscriptional regulators of mRNAs. Binding to their target sites, which are mostly located within the 3'-untranslated region (3'-UTR) of mRNA transcripts, they modulate mRNA expression and stability. Until today almost all human mRNA transcripts are known to harbor at least one miRNA target site with an average of over 20 miRNA target sites per transcript. Among 5,101 GWAS-identified sentinel single nucleotide polymorphisms (SNPs) that correspond to 18,884 SNPs in linkage disequilibrium (LD) with the sentinels (r2 ? 0.8) we identified a significant overrepresentation of SNPs that affect the 3'-UTR of genes (OR?=?2.33, 95% CI?=?2.12-2.57, P < 10(-52)). This effect was even stronger considering all SNPs in one LD bin a single signal (OR?=?4.27, 95% CI?=?3.84-4.74, P < 10(-114)). Based on crosslinking immunoprecipitation data we identified four mechanisms affecting miRNA regulation by 3'-UTR mutations: (i) deletion or (ii) creation of miRNA recognition elements within validated RNA-induced silencing complex binding sites, (iii) alteration of 3'-UTR splicing leading to a loss of binding sites, and (iv) change of binding affinity due to modifications of 3'-UTR folding. We annotated 53 SNPs of a total of 288 trait-associated 3'-UTR SNPs as mediating at least one of these mechanisms. Using a qualitative systems biology approach, we demonstrate how our findings can be used to support biological interpretation of GWAS results as well as to provide new experimentally testable hypotheses.

SUBMITTER: Arnold M 

PROVIDER: S-EPMC3350471 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature