Why do we need genome-wide association studies?
To answer that, we first need to look at the kinds of genetic changes that have previously been studied by medical geneticists. These have usually been 'single-gene disorders', which result from mutations in single genes, where an individual with a mutant allele of the gene (in the homozygous state for a recessive disorder) has the disease with a hundred percent probability. Thus, an individual homozygous for the sickle-cell allele of the beta-globin gene will always have sickle-cell anemia (Figure 1). When all individuals with the disease genotype have the disease, we describe such a mutation as one hundred percent penetrant. When the penetrance is less, there are individuals who have the predisposing genotype, but do not have the disease. This is because other genes play a role in the determination of the disease, or because of the effects of the environment. This makes the mapping of the gene causing the disease using pedigree information (as illustrated in Figure 1) more difficult.
Pedigrees. Here a square represents a male, and a circle a female. (a) For a dominant disorder, such as Huntington's disease, represented by the allele symbol H, an individual need only inherit the mutant allele from one parent (that is, be heterozygous) to be affected. In such cases, affected individuals almost always are in fact heterozygous for the mutant allele, and they transmit it, and the disease, to half the offspring. (b) For a recessive disorder, in this case sickle cell anemia, shown by the βS allele symbol, the disease is seen only in individuals homozygous for the allele (that is, who have inherited the allele from both parents); they are typically the offspring of two heterozygotes (carriers of the disease).
Where the penetrance is very low, it is virtually impossible to map genes using pedigrees, and here we enter the world of multifactorial disorders, where the presence or absence of the disease is influenced by many genetic differences and also by the environment. The role of genes in determining whether individuals have the disease can still be important, and this is measured by the 'heritability' of the disease, which is the proportion of the determination of the disease that is caused by genetic rather than environmental differences. Heritability for such disorders is measured through the correlations between relatives, most powerfully using monozygotic (identical) and dizygotic twins. Single-gene disorders tend to be rare, whereas many important multifactorial diseases, including, for example, hypertension, diabetes and schizophrenia, have much higher frequencies in the population, but still have high heritabilities. The goal of genome-wide association studies (GWAS) is to understand common multifactorial diseases and the genes that predispose us to them.