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Science. 2016 Apr 29;352(6285):600-4. doi: 10.1126/science.aad9417. Epub 2016 Apr 28.

RNA splicing is a primary link between genetic variation and disease.

Author information

1
Department of Genetics, Stanford University, Stanford, CA, USA.
2
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
3
Department of Computer Science, Stanford University, Stanford, CA, USA. Department of Radiology, Stanford University, Stanford, CA, USA.
4
Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
5
Department of Human Genetics, University of Chicago, Chicago, IL, USA. gilad@uchicago.edu pritch@stanford.edu.
6
Department of Genetics, Stanford University, Stanford, CA, USA. Department of Biology, Stanford University, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. gilad@uchicago.edu pritch@stanford.edu.

Abstract

Noncoding variants play a central role in the genetics of complex traits, but we still lack a full understanding of the molecular pathways through which they act. We quantified the contribution of cis-acting genetic effects at all major stages of gene regulation from chromatin to proteins, in Yoruba lymphoblastoid cell lines (LCLs). About ~65% of expression quantitative trait loci (eQTLs) have primary effects on chromatin, whereas the remaining eQTLs are enriched in transcribed regions. Using a novel method, we also detected 2893 splicing QTLs, most of which have little or no effect on gene-level expression. These splicing QTLs are major contributors to complex traits, roughly on a par with variants that affect gene expression levels. Our study provides a comprehensive view of the mechanisms linking genetic variation to variation in human gene regulation.

PMID:
27126046
PMCID:
PMC5182069
DOI:
10.1126/science.aad9417
[Indexed for MEDLINE]
Free PMC Article

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