An utter refutation of the "fundamental theorem of the HapMap".

The International HapMap Project was proposed in order to quantify linkage disequilibrium (LD) relationships among human DNA polymorphisms in an assortment of populations, in order to facilitate the process of selecting a minimal set of markers that could capture most of the signal from the untyped markers in a genome-wide association study. The central dogma can be summarized by the argument that if a marker is in tight LD with a polymorphism that directly impacts disease risk, as measured by the metric r(2), then one would be able to detect an association between the marker and disease with sample size that was increased by a factor of 1/r(2) over that needed to detect the effect of the functional variant directly. This "fundamental theorem" holds, however, only if one assumes that the LD between loci and the etiological effect of the functional variant are independent of each other, that they are statistically independent of all other etiological factors (in exposure and action), that sampling is prospective, and that the estimates of r(2) are accurate. None of these are standard operating assumptions, however. We describe the ramifications of these implicit assumptions, and provide simple examples in which the effects of a functional variant could be unequivocally detected if it were directly genotyped, even as markers in high LD with the functional variant would never show association with disease, even in infinite sample sizes. Both theoretical and empirical refutation of the central dogma of genome-wide association studies is thus presented.