Mutations that give rise, in a reproducible way, to rare but clearly defined abnormalities, such as albinism, hemophilia, or congenital deafness, can often be identified by studies of affected families. Such single-gene, or monogenic, disorders are often referred to as Mendelian because their pattern of inheritance is easy to track. Moreover, individuals who inherit the causative mutation will exhibit the abnormality irrespective of environmental factors such as diet or exercise. But for many common diseases, the genetic roots are more complex. Instead of a single allele of a single gene, such disorders stem from a combination of contributions from multiple genes. And often, environmental factors have strong influences on the severity of the disorder. For these multigenic conditions, such as diabetes or arthritis, population studies are often helpful in tracking down the genes that increase the risk of getting the disease.
In population studies, investigators collect DNA samples from a large number of people who have the disease and compare them to samples from a group of people who do not have the disease. They look for variants—SNPs, for example— that are more common among the people who have the disease. Because DNA sequences that are close together on a chromosome tend to be inherited together, the presence of such SNPs could indicate that an allele that increases the risk of the disease might lie nearby (Figure 8–51). Although, in principle, the disease could be caused by the SNP itself, the culprit is much more likely to be a change that is merely linked to the SNP as part of a haplotype block.
Such genome-wide association studies have been used to search for genes that predispose individuals to common diseases, including diabetes, coronary artery disease, rheumatoid arthritis, and even depression. For many of these conditions, the DNA polymorphisms identified increase the risk of disease only slightly. Moreover, environmental factors (diet, exercise, for example) play an important role in the onset and severity of the disease. Nonetheless, the identification of genes affected by these polymorphisms is leading to a mechanistic understanding of some of our most common disorders.
Genomics Is Accelerating the Discovery of Rare Mutations That Predispose Us to Serious Disease
The genetic variants that have thus far allowed us to identify some of the genes that increase our risk of disease are common ones. They arose long ago in our evolutionary past and are now present, in one form or another, in a substantial portion (1% or more) of the population. Such polymorphisms are thought to account
Figure 8–51 Genes that affect the risk of developing a common disease can often be tracked down through linkage to SNPs. Here, the patterns of SNPs are compared between two sets of individuals—a set of healthy controls and a set affected by a particular common disease. A segment of a typical chromosome is shown. For most polymorphic sites in this segment, it is a random matter whether an individual has one SNP variant (red vertical bars) or another (blue vertical bars); this same randomness is seen both for the control group and for the affected individuals. However, in the part of the chromosome that is shaded in darker gray, a bias is seen: most normal individuals have the blue SNP variants, whereas most affected individuals have the red SNP variants. This suggests that this region contains, or is close to, a gene that is genetically linked to these red SNP variants and that predisposes individuals to the disease. Using carefully selected controls and thousands of affected individuals, this approach can help track down disease-related genes, even when they confer only a slight increase in the risk of developing the disease.
for about 90% of the differences between one person’s genome and another’s. But when we try to tie these common variants to differences in disease susceptibility or other heritable traits, such as height, we find that they do not have as much predictive power as we had anticipated: thus, for example, most confer relatively small increases—less than twofold—in the risk of developing a common disease.