The finding of a significant association between a variant and a phenotype may be due several factors. The variant itself may modify function by altering the coding sequence of the gene, the stability of the resulting mRNA (Duan, Wainwright et al. 2003), or the regulation of gene expression. Regulatory variants may be found far upstream of genes. For example, a number of variants have been identified upstream of the SOX9 gene which are associated with the palatal lesion Pierre Robin sequence (Benko, Fantes et al. 2009). One variant is located 1.44 million nucleotides upstream of SOX9 and alters several predicted transcription binding sites. Other examples include two variants found upstream of the SHH gene. One is located one million nucleotides upstream of the SHH gene (Lettice, Heaney et al. 2003) and was found to be associated with preaxial polydactyly, while the other is located 470,000 nucleotides upstream and was associated with holoprosencephaly (Jeong, Leskow et al. 2008). Using 11,446 genes in a Bayesian hierarchical model, the Pritchard group found that 5% of the quantitative trait loci for gene expression (eQTLs) were located more than 20,000 nucleotides upstream of the transcription start sites (Veyrieras, Kudaravalli et al. 2008).
