One line of evidence that suggests that synthetic associations do not underlie many reported GWAS associations is provided by linkage scans that have been conducted in the past. The genetic model that underpins synthetic association (allelic heterogeneity caused by several low-frequency variants with larger effects than commonly seen in GWAS) is highly tractable by linkage analysis, which combines information from all causal variants at a particular locus. This relationship is highlighted by the widely replicated linkage between the NOD2 gene and CD, which is driven by three independent, low-frequency causal variants (48–50) which cause a synthetic association signal in GWAS of CD (Fig. 1). NOD2 is the exception that proves the rule that, despite many attempts, very few replicable linkages to complex diseases have been discovered (51). This dearth of findings is informative when considering the likelihood of synthetic associations because it rules out a class of genetic models from playing a substantial role in complex disease.
