Lee Responds to “Testing for Hardy-Weinberg Disequilibrium”

I appreciate Weinberg and Morris’ thoughtful commentary (1) on my paper (2). In their article, they put my work under the perspective of gene mapping in the postgenomic era. I share the same view with them that the method proposed in my paper amounts to a tree-shaking approach to harvesting the high-hanging fruit (a low-cost approach to generating hypotheses aimed at localizing diseasesusceptibility genes for complex human diseases). However, some issues raised by Weinberg and Morris (1) deserve scrutiny. These are 1) the power of the HardyWeinberg disequilibrium test (HWT) when a single-nucleotide polymorphism is a “marker” but is not a diseasesusceptibility “gene” itself; 2) the utility of the proposed method as a gene-localization tool; and 3) the false alarm due to unmeasured ethnicity. To address the first issue, consider a marker, M, which is in linkage disequilibrium with a disease-susceptibility gene, A. Jiang et al. (3) showed that, for the M marker, the HardyWeinberg disequilibrium coefficient in the affected population is (with the notations changed to be consistent with my paper (2)):