Short tandem repeat polymorphisms create an abundant source of expression variability. M. Gymrek1,2,3,4, S. Georgiev5, B. Markus1, J. Chen2, P. Villarreal1, J. Pritchard5,6, Y. Erlich1 1) Whitehead Institute, Cambridge, MA; 2) Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA; 3) Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA; 4) Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA; 5) Department of Human Genetics, University of Chicago, Chicago, IL; 6) Howard Hughes Medical Institute, Chevy Chase, MD.
A central goal in genomics is to elucidate the genetic architecture of complex traits. So far, efforts to discover eQTLs (expression Quantitative Trait Loci) have been mainly focused on the contribution of SNPs and CNVs to gene expression. A few dozen single gene studies in human and model organisms have suggested that short tandem repeat (STR) variations can modulate expression of nearby transcripts. Here, we report the first genome-wide survey to identify STRs that affect gene expression. We analyzed STR variations across hundreds of samples from the 1000 Genomes Project across nine populations using a custom algorithm and performed association tests with the expression levels of nearby transcripts. This process identified significant associations between STR variations and expression profiles (eSTRs) of more than 3,000 genes. These associations were replicated across populations and on orthogonal expression assays (RNA-sequencing and expression array). Predicted eSTRs are found near transcription start sites, are strongly enriched in annotated promoter and enhancer elements, and fall into regions predicted by chromatin marks to be active regulatory regions. Moreover, fine-mapping techniques indicate that the eSTR association signals are unlikely to stem from tagging nearby SNPs or other variations in linkage disequilibrium. These loci may provide a novel set of regulatory variants that can help explain the genetic architecture of gene expression and contribute to the heritability of complex traits.
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