Another prediction made by the synthetic association hypothesis is that the most significantly associated common variant identified by GWAS might be located several megabases away from the underlying low-frequency functional variants. The empirical properties of linkage disequilibrium between low-frequency and common variants are not fully understood, although the complete 1000 Genomes project (http://www.1000genomes.org/) will soon provide information necessary to evaluate this question directly. Nevertheless, two indirect pieces of evidence suggest that most GWAS hit SNPs are within a few hundred kilobases (and many within tens of kilobases) of their tagged functional alleles. First, a large number of GWAS signals across a variety of traits are nearby to genes previously established to cause Mendelian forms of the same trait (55). Secondly, genes involved in key pathways repeatedly arise in GWAS of some diseases. For example, 8 of 10 proteins involved in the Th17-differentiation signalling pathway have been associated with one or more auto-inflammatory diseases (56). As with many aspects relating to the evaluation of the prevalence of synthetic associations, deeper sequence data sets will be needed to fully answer the question
