Human gene expression levels have a strong heritable component [1-4]. At some genes, the variance in gene expression levels is an order of magnitude greater between unrelated individuals, than between identical twins [5]. Quantitative mRNA levels are key regulators of phenotype and represent a link between genetic variation and phenotypic alterations. A term first introduced by Jansen & Nap [6], genetical genomics aims to identify the genetic variants that affect gene expression. By treating gene expression as a quantitative trait it is possible to correlate gene transcript expression levels with genomic locations such that expression quantitative trait loci (eQTLs) can be identified [7]. In the human genome, cis associations, where a genetic variant affects a transcript that maps to the same locus, have been predominantly reported [3,8]. Trans effects, where the genetic variant is distant to the transcript loci, are much harder to convincingly identify due to inherent multiple testing problems. Analysis of trans effects involves several magnitudes more statistical tests than for cis effects. Although individual studies have reported human trans associations, no effects have been convincingly replicated in multiple studies identified for the same transcript and variant [1,9,10].
