E pluribus unum

A few diseases can be traced to specific genetic variants. The nerve degeneration of Huntington's Disease, for example, arises exclusively from alterations of either copy of a gene on chromosome 4. This gene specifies a protein that is now called huntingtin. Such diseases are referred to as Mendelian, since they follow the simple rules of inheritance that Gregor Mendel observed in his pea plants.

For most diseases, though, it has proved difficult to find individual genes that explain much of the risk. Instead, the growing evidence from large-scale studies is that many variants contribute, each contributing only weakly. Even then, the genes alone do not condemn a person to the disease, which may also depend on microbes or non-living elements of the environment or on lifestyle. These "complex" diseases include all of the biggies, like heart disease and stroke, cancers, and many mental illnesses.

In some ways, the failure of the "one-gene/one-disorder" hypothesis shouldn't be too surprising. After all, a gene that reliably causes a fatal disease should have been largely weeded out by natural selection. Huntington's disease avoids this fate because it usually appears late in life, often after people have already had children (including, fortunately for us, Arlo Guthrie). Sickle-cell anemia persists because people with a single variant gene are resistant to malaria, although two copies cause the disease.

Nonetheless, lots of other diseases have an import genetic component, which can be determined by comparing the disease rate for close relatives. For example, if pairs of "identical" twins are more likely to both get a disease than are fraternal twins, the difference presumably arises because they share their entire genome, rather than only half.

For simple Mendelian diseases, researchers have extended this approach to locate where the disease gene resides in the chromosomes. This "linkage" analysis looks at which close relatives inherited a disease, and what known chromosome features they also inherited. This technique was applied in the 1980s to locate the Huntington's gene by testing dozens of residents of a Venezuelan village that had unusually many cases.

But human populations aren't particularly well suited for linkage studies. People don't have a lot of children, and they resist attempts at controlled breeding. As a result, it's hard to see weak genetic effects.

To get more subjects, researchers use association studies, which compare the genetics of unrelated individuals. Historically, you really had to know where to look to make associations studies work. But in the past few years researchers have done dozens of "genome-wide association studies," or GWAS, that look without prejudice across the entire human genome.

These studies are tricky. For one thing, since they monitor perhaps a million genetic markers at once, the chances are good that a marker will correlate with the disease by dumb (bad) luck. In individual experiments, researchers traditionally ignore a result if the probability of it arising by chance isn't less than 5% (P<0.05). For testing a million markers, they might need to ignore a result unless the effect is so strong that the probability that it arose by chance is less than perhaps 5x10^-8. To get such a convincing effect requires a lot of human subjects, generally hundreds or thousands. Even so, GWAS results often fail to recur when someone else tries the experiment.

Nonetheless, some genome-wide studies, like two for Alzheimer's I wrote about recently, have uncovered genes repeatedly associated with disease. In addition to variations of the DNA sequence, these studies often include structural variants such as copy-number variations, as well as "epigenetic" tags that change the expression of particular DNA regions. In spite of finding some likely genetic suspects, though, the total effect of all of the known variants is generally less than the known genetic component of these complex diseases. Researchers are actively debating the causes of this discrepancy; probably part of it comes because there are other contributions that are too weak to be seen in these studies.

Because complex diseases depend on the small contributions of many genetic variants, as well as the environment, buying your personal genome often won't tell you much definitive. But by studying these variants, and the way their effects interact in cells, researchers are learning a great deal about the nature of the diseases, including potential strategies for treating them.