In addition to pathological mutations sensu stricto, introns also harbour functional polymorphisms that can influence the expression of the genes that host them. Some of these intronic variants may also confer susceptibility to disease or otherwise modulate the genotype-phenotype relationship. For the reasons discussed above, it is very likely that such variants will have been seriously under-ascertained to date. Although most of these variants are single nucleotide polymorphisms (SNPs), others may be of the insertion/deletion type [8]. With the advent of genome-wide association studies (GWAS), an increasing number of potentially functional intronic variants are being identified [9]. In the majority of cases, however, it is unclear whether such variants are of direct functional significance, as opposed to simply being in linkage disequilibrium with another (as yet unidentified) functional SNP in the vicinity [10]. Even when GWAS studies deem a newly identified intronic polymorphism to be 'functional', it should be appreciated that such a term may often be ascribed solely on the basis of an observed association between a specific allele and a plasma protein level, enzymatic activity or a clinical/laboratory
