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Am J Hum Genet. 2017 Apr 6;100(4):605-616. doi: 10.1016/j.ajhg.2017.03.002. Epub 2017 Mar 23.

Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues.

Author information

1
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: xuliu@hsph.harvard.edu.
2
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
4
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Bioinformatics and Integrative Genomics, Harvard University, Boston, MA 02115, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Bioinformatics Research Center, Departments of Statistics and Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
7
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm 17177, Sweden.
8
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Electronic address: aprice@hsph.harvard.edu.

Abstract

Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.41×), conserved regions (4.67×), and four histone marks (p < 5 × 10-5 for all enrichments); local enrichments were similar across the 15 tissues. We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.47×), conserved regions (4.51×), and two histone marks (p < 3 × 10-7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

KEYWORDS:

eQTLs; functional annotation; gene expression regulation; heritability

PMID:
28343628
PMCID:
PMC5384099
DOI:
10.1016/j.ajhg.2017.03.002
[Indexed for MEDLINE]
Free PMC Article

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