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Nat Genet. 2016 Jan;48(1):22-9. doi: 10.1038/ng.3461. Epub 2015 Dec 7.

Abundant contribution of short tandem repeats to gene expression variation in humans.

Gymrek M1,2,3,4, Willems T1,4,5, Guilmatre A6,7, Zeng H8, Markus B1, Georgiev S9, Daly MJ3,10, Price AL3,11,12, Pritchard JK9,13, Sharp AJ6, Erlich Y1,4,14,15.

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
2
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
New York Genome Center, New York, New York, USA.
5
Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
6
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
7
Department of Pediatric Hematology, Robert Debré Hospital, Paris, France.
8
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
9
Department of Genetics and Biology, Stanford University, Stanford, California, USA.
10
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
11
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
12
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
13
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
14
Department of Computer Science, Fu Foundation School of Engineering, Columbia University, New York, New York, USA.
15
Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, USA.

Abstract

The contribution of repetitive elements to quantitative human traits is largely unknown. Here we report a genome-wide survey of the contribution of short tandem repeats (STRs), which constitute one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from that of linked SNPs and indels and found that eSTRs contribute 10-15% of the cis heritability mediated by all common variants. Further functional genomic analyses showed that eSTRs are enriched in conserved regions, colocalize with regulatory elements and may modulate certain histone modifications. By analyzing known genome-wide association study (GWAS) signals and searching for new associations in 1,685 whole genomes from deeply phenotyped individuals, we found that eSTRs are enriched in various clinically relevant conditions. These results highlight the contribution of STRs to the genetic architecture of quantitative human traits.

PMID:
26642241
PMCID:
PMC4909355
DOI:
10.1038/ng.3461
[Indexed for MEDLINE]
Free PMC Article

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