Expression quantitative trait loci (eQTLs) are genomic loci that contribute to variation in expression levels of mRNAs.
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Distant and local, trans- and cis-eQTLs, respectively
Expression traits differ from most other classical complex traits in one important respect—the measured mRNA or protein trait is almost always the product of a single gene with a specific chromosomal location. eQTLs that map to the approximate location of their gene-of-origin are referred to as local eQTLs. In contrast, those that map far from the location of their gene of origin, often on different chromosomes, are referred to as distant eQTLs. Often, these two types of eQTLs are referred to as cis and trans, respectively, but these terms are best reserved for instances when the regulatory mechanism (cis vs. trans) of the underlying sequence has been established. The first genome-wide study of gene expression was carried out in yeast and published in 2002. Many expression QTL studies followed in plants and animals, including humans. The initial wave of eQTL studies employed microarrays to measure genome-wide gene expression; more recent studies have employed massively parallel RNA sequencing.
Some cis eQTLs are detected in many tissue types but the majority of trans eQTLs are tissue-dependent (dynamic). eQTLs may act in cis (locally) or trans (at a distance) to a gene. The abundance of a gene transcript is directly modified by polymorphism in regulatory elements. Consequently, transcript abundance might be considered as a quantitative trait that can be mapped with considerable power. These have been named expression QTLs (eQTLs) The combination of whole-genome genetic association studies and the measurement of global gene expression allows the systematic identification of eQTLs. By assaying gene expression and genetic variation simultaneously on a genome-wide basis in a large number of individuals, statistical genetic methods can be used to map the genetic factors that underpin individual differences in quantitative levels of expression of many thousands of transcripts. Studies have shown that single nucleotide polymorphisms (SNPs) reproducibly associated with complex disorders as well as certain pharmacologic phenotypes are found to be significantly enriched for eQTLs, relative to frequency-matched control SNPs.
Detecting eQTLs
Mapping eQTLs is done using standard QTL mapping methods that test the linkage between variation in expression and genetic polymorphisms. The only considerable difference is that eQTL studies can involve a million or more expression microtraits. Standard gene mapping software packages can be used, although it is often faster to use custom code such as QTL Reaper or the web-based eQTL mapping system GeneNetwork. GeneNetwork hosts many large eQTL mapping data sets and provide access to fast algorithms to map single loci and epistatic interactions. As is true in all QTL mapping studies, the final steps in defining DNA variants that cause variation in traits are usually difficult and require a second round of experimentation. This is especially the case for trans eQTLs that do not benefit from the strong prior probability that relevant variants are in the immediate vicinity of the parent gene. Statistical, graphical, and bioinformatic methods are used to evaluate positional candidate genes and entire systems of interactions.