The Genetic Basis of Complex Traits: Rare Variants or Common Gene, Common Disease

The goal of the Human Genome Project and the subsequent HapMap Project was to accelerate the pace at which genes for complex human traits were discovered. Elated by the early successes from cloning disease genes for monogenic disorders, the architects of the projects reasoned that complex human diseases were tractable to positional cloning methods. However, a schism emerged in the field, with hot debates regarding two competing hypotheses being publicly waged. These opposing hypotheses pertained to the anticipated allelic spectrum and frequency of disease variants associated with common, complex disease. The common disease, common variant hypothesis (CD/CV) stated that a few common allelic variants could account for the genetic variance in disease susceptibility, whereas the rare variant (CD/RV) hypothesis stated that DNA sequence variation at any gene causing disease could encompass a wide range of possibilities, with the most extreme being that each mutation is only found once in the population. The practical consequence of the debate can be broken into two parts. If the CD/CV hypothesis is true, then application of the positional cloning paradigm to map disease genes would be eminently more feasible, as a common allele would be easier to locate. Conversely, if rare variants cause common disease, then identifying these genetic susceptibility variants would be challenging. Whether a disease is caused by rare or common alleles will have an impact on clinical applications, such as designing prognostic assays, or planning therapeutic interventions; fewer susceptibility alleles will simplify assay design, and the associated reduction in costs would amortize if a universally applicable therapy can be deployed. A current review of the literature suggests that both these hypotheses are correct, depending on the gene and disease examined. Although the controversial debate is revived with the identification of each new disease gene, the time has come to integrate both hypotheses in a manner that best explains biological variation in natural populations. The allelic spectrum of variation in a particular gene may be better explained by one of the two hypotheses but, for a multifactorial trait, a composite encompassing all influential genes needs to be constructed.