The second possible explanation for the clear excess of candidate mechanisms in the case of autoimmune diseases is more fundamental and relates to the growing recognition of the importance of rare variants in common disease [22–24]. It is generally assumed that when a common SNP is associated with disease in a genome-wide study, that it, or some other common variant in LD with it, is responsible for the association. It is theoretically possible, however, that many of the associations observed are not due to single common variants, but rather due to a constellation of more rare disease-causing variants that happen to occur, by chance, more frequently along with one of the common alleles at given SNP as opposed to the other. In such a case, the signal of association credited to a common SNP is actually a synthetic association resulting from the contributions of multiple rare SNPs. In such cases a screen for a common SNP associated with an underlying biological effect (such as expression or splicing) is not likely to identify a causal site. Our failure to identify any
