Genetic variability in gene expression may occur at many stages: transcription, messenger RNA (mRNA) stability, and splicing or translation efficiency. In each of these instances, the underlying variability would be expected to occur in different DNA elements that may have element-specific sequence motifs and should be distinguishable by their effects on cellular RNA species. Tissue-specific genomewide analyses of gene expression offer a starting point for parsing the various possibilities.26 This approach has been particularly helpful in understanding the effect of susceptibility variants in immune-mediated disease, such as asthma, because the lymphocyte (which is pivotal to the pathological analysis of such disease) is easily accessible,27 although human fat tissue28 and human brain tissue29 obtained at autopsy have also been used. Three examples of this approach illustrate its power: a haplotype associated with asthma also shows an association with lymphoblastoid expression of the proteins ORMDL3 and GSDML,27,30 genetic variants that are associated with obesity are also associated with the expression of their cognate mRNAs in adipose tissue,28 and a variant of MAPT (encoding tau) that is associated with progressive supranuclear palsy is also associated with MAPT mRNA expression.29,31,32
