Most genetic diseases do not follow a Mendelian paradigm; instead they are multifactorial having biological components that are both in the host (biological variation) and in the environment (exposure to experiences that are selective and impinge on health). In addition to alleles that confer susceptibility (for resistance) under certain conditions, there could be a constellation of alleles at different loci affecting proteins that must interact, in this way accounting for a complex trait. This chapter addresses, in a brief way, how one begins to approach mapping the genomic bases of complex traits.
Multifactorial diseases are common quantitative traits underpinned by the interaction of common alleles of several genetic polymorphisms, each a quantitative trait locus (QTL), and by environmental factors. Affected individuals have inherited a threshold of liability, the penetrance of which is usually much less than 100 percent. The number and interactions of disease protective and predisposing alleles that are inherited from both parents determine the threshold, and the penetrance is affected by developmental, stochastic, and environmental factors. With the emergence of dense, easily typed genetic maps, the search for genes with etiologically associated alleles with measurable effects is in full swing. But because most QTLs have small effects, the approach of meiotic mapping used successfully in rare, fully penetrant, single-gene diseases is not practical. Rapid progress in identifying the molecular basis of common disease requires a catalogue of all of the common polymorphisms in or near all genes, a goal currently within the budgetary and technical grasp of the genome project, combined with large, well-characterized collections of patients, relatives, and genetically-matched controls. The difficulties encountered in the genetic and functional analysis of human common disease continue to highlight the necessity of mapping and identifying QTLs in rodent models of these diseases. Progress and strategies in the identification of etiologic variants in common disease is illustrated using type 1 diabetes as an example.
Penrose introduced the term “multifactorial” to describe traits or diseases that did not exhibit a clear Mendelian mode of inheritance owing to their reduced penetrance.1 Possession of the disease-associated genotype bestows only a risk of developing the disorder. It is presumed that these traits are the result of the combined action of several or many genetic variants or alleles. Alleles of QTL are common in the general population and mostly ancient in origin, and account for a large proportion of the normal variation within the population. Certain combinations of QTLs, however, constitute the predisposition to multifactorial diseases such as diabetes, asthma, autoimmunity, obesity, and cardiovascular disease, which are “threshold characters.”2 Individual QTL alleles or polymorphisms have modest or subtle effects compared to the mutant alleles that cause rare Mendelian diseases. Mutant alleles usually have major consequences on gene functions.
Cystic fibrosis is a clear example of ...