‘Synthetic association’ describes the situation where the association of a common variant with a disease is actually due to linkage disequilibrium between the common variant and several disease-promoting rare variants that happen to segregate on the same haplotype50. Thus, a common variant present in 20% of cases that mathematically explains one percent of disease susceptibility may actually simply report the activity of two or three rare variants that each substantially elevate risk in one or two percent of the cases. Until this year rare variants been excluded from the major whole genome genotyping platforms, so there has been no way to systematically document their contribution. Synthetic association is not expected to account for most of the missing heritability19, 51, but this type of effect must always be considered as an explanation for apparent common-variant effects52.
