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Genetics. 2016 Nov;204(3):1057-1064. doi: 10.1534/genetics.115.177246. Epub 2016 Oct 7.

Discovering Single Nucleotide Polymorphisms Regulating Human Gene Expression Using Allele Specific Expression from RNA-seq Data.

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Department of Computer Science, University of California, Los Angeles, California 90095-1596.
Department of Human Genetics, University of California, Los Angeles, California 90095-1596.
Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 91904, Israel.
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142.
Department of Computer Science, University of California, Los Angeles, California 90095-1596


The study of the genetics of gene expression is of considerable importance to understanding the nature of common, complex diseases. The most widely applied approach to identifying relationships between genetic variation and gene expression is the expression quantitative trait loci (eQTL) approach. Here, we increased the computational power of eQTL with an alternative and complementary approach based on analyzing allele specific expression (ASE). We designed a novel analytical method to identify cis-acting regulatory variants based on genome sequencing and measurements of ASE from RNA-sequencing (RNA-seq) data. We evaluated the power and resolution of our method using simulated data. We then applied the method to map regulatory variants affecting gene expression in lymphoblastoid cell lines (LCLs) from 77 unrelated northern and western European individuals (CEU), which were part of the HapMap project. A total of 2309 SNPs were identified as being associated with ASE patterns. The SNPs associated with ASE were enriched within promoter regions and were significantly more likely to signal strong evidence for a regulatory role. Finally, among the candidate regulatory SNPs, we identified 108 SNPs that were previously associated with human immune diseases. With further improvements in quantifying ASE from RNA-seq, the application of our method to other datasets is expected to accelerate our understanding of the biological basis of common diseases.


Allele specific expression; causal variants; expression quantitative trait loci

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