The common disease common variant concept

Abstract

AbstractComplex genetic disease traits comprise the majority of chronic disease traits that afflict industrialized societies. The common disease–common variant hypothesis stems from a consideration of the recent explosive numerical increase in the human population and seeks to address vital issues that impact on the likely success or failure of association strategies in the analysis of complex human disease traits.In comparison with simple Mendelian traits, only very limited progress has been made in determining the disease alleles that contribute to the development of complex, polygenic disease traits. For the most part, the mutations that underlie monogenic disorders are present at low frequencies in all or most human populations. They frequently exhibit a complex allelic spectrum; that is, multiple mutations in a single gene may relate to the same disease phenotype. Do complex disease traits exhibit similar complexities of allelic spectra? And how frequent are the causal alleles that contribute to their development in the population? Insufficient data are available to answer these questions directly. However, population genetics theory can be used to show that relatively common disease susceptibility alleles (frequency at least 5%) present in the human population prior to the recent numerical expansion will be present at a similar frequency in the modern human population since there has been insufficient time for these alleles to be “diluted” out of the population or for their allelic complexity to have radically increased as a consequence of there being new mutations. Thus, it can be argued that disease susceptibility alleles that happened to be relatively common in the early human population will still be so today. Since the selection pressures on the founding human population were very different from those experienced in industrialized societies, it is plausible that disease susceptibility alleles for complex traits may have been relatively common. In essence, this describes the essence of the common disease–common variant disease hypothesis. Indeed, it can be argued that some common variants may convey some from of selective advantage. Possible examples include variants that would convey metabolic efficiency in early populations, yet predispose to obesity and diabetes in modern societies; it can be similarly argued that variants that improve resistance to infection may promote autoimmunity. However, proof of this concept remains to be established.