Now that the sequence of the 30,000 or so human genes has been mapped, one of the biggest challenges facing researchers is identifying genes that conspire to make some people susceptible to common yet complex diseases, from cancer and heart disease to disorders of brain function.
One place to start is to study candidate genes that already have been implicated in disease. For example, drugs used to treat attention deficit hyperactivity disorder (ADHD) primarily affect regulation of the neurotransmitter dopamine, which transmits messages between nerve cells. Thus, it is reasonable to look at genes involved in dopamine regulation and, in particular, for polymorphisms, or variations in the DNA sequences of these genes that are found in the population.
Genetic polymorphisms that occur more frequently in families of children with ADHD than in unaffected families suggest that, while each variation alone may not be sufficient to increase risk, the combination of polymorphisms may be important in the development of the disorder.
Another way to search for disease-related genes is to use markers to scan all of the 23 pairs of chromosomes contained by normal human cells, looking for regions that are inherited more frequently by people who have a certain disease than would be expected to occur by chance, or to cull through the millions of single nucleotide polymorphisms, or changes in a single letter of the DNA code, that are estimated to occur throughout the entire human genome.
This “needle in a haystack” approach is made possible by today’s powerful supercomputing capacity, which can rapidly determine complex, statistically significant associations between dozens of genetic variations.
Using these statistical techniques, researchers also can look for interactions between genes and the environment. “Association analyses” are often used to determine whether a combination of genetic polymorphisms and environmental factors are more common in people who are diagnosed with a particular disease than in a “control group” of people who aren’t.
For example, a study published this summer in the journal Science found that people born with a variant of a gene important in the regulation of the neurotransmitter serotonin are significantly more likely to become depressed after experiencing four or more stressful life events, than are people who don’t have the polymorphism. This finding suggests that the presence of genetic variations alone may not be sufficient to cause some complex diseases – they require an environmental “trigger.”
“Essentially, genetics deals the cards, and environment plays the hand,” says Jonathan L. Haines, Ph.D., director of Vanderbilt Center for Human Genetics Research.