DOI: 10.1093/aje/kwg151 Invited Commentary: Testing for Hardy-Weinberg Disequilibrium Using a Genome Single-Nucleotide Polymorphism Scan Based on Cases Only

Classical methods for localizing genes based on pedigrees and linkage have served well for genes that are “Mendelian,” that is, where genotype and phenotype are closely related. Geneticists now recognize that these methods do not work so well when applied to the more common, multifactorial diseases. Risch comments, “The gene mutations studied by Mendel, and those more recently discovered by positional cloning, are those with large effect and strong genotype-phenotype correlations. They are effectively the ‘low-hanging fruit ’ that are easy to harvest. Now, however, we are left with the great majority of the fruit at the top of the tree, with no obvious way to reach it ” (1, p. 850). At the same time, the mapping of the human genome, together with new genotyping technologies, has sparked interest in whole-genome approaches for finding the relatively prevalent alleles with low penetrance that underlie susceptibility to common diseases. To identify such genes, one must be able to correlate the genetic variation in a population with variation in risk of disease. Meanwhile, the extent of variation in the human genome seems daunting. With the number now standing at almost 2 million, the number of known single-nucleotide polymorphisms (SNPs) continues to rise (2) (se