It has recently been argued that single rare causal variants and/or collections of multiple different rare variants on unrelated haplotypes may create “synthetic associations” of common variants with disease risk [19]–[21]. One prediction of this model is that the associations with common variants will not be consistent across populations (since many of the mutations will be young in age, and post-date the migrations that led to the founding of modern continental populations). Type 2 diabetes has been specifically discussed as a possible case in which synthetic associations might be operative, based on the lack of statistical significance in very small studies that examined allelic associations for T2D in multi-ethnic samples.
