Schizophrenia, which afflicts about one percent of the world’s population, is often said to “run in families.” That’s why it’s common for children or siblings of people with schizophrenia to feel tremendous worry or even anger that their family member’s inherited illness may foreshadow their own. But does the fact that schizophrenia can be inherited mean that a person is a prisoner of his or her genes?

“I think destiny is determined by genes and environment—it’s both,” Dr. Michael Egan maintains. He’s a staff physician and Principal Investigator in the Clinical Brain Disorders Branch at the National Institute of Mental Health in Bethesda, Maryland.

“Schizophrenia is a so-called ‘complex illness,’ as are most diseases, like, for example heart disease or diabetes,” Dr. Egan continues. “They appear to have many causes—including multiple genes and environmental factors such as drug abuse, head injury, or even, possibly, infections, as well as a person’s behavior. These multiple causes are all in play together, influencing each other.”

While genes are not all-powerful, they certainly hold formidable power. Dr. Egan and his multidisciplinary team are currently studying the genetics of schizophrenia, research that, in 2003, Science Magazine called a “Breakthrough of the Year.” Among the team’s activities is its work with over 450 families to learn how a number of candidate genes affect brain physiology and function, and how these factors, when combined, could raise a person’s risk for schizophrenia. Dr Egan and his team are already applying their findings in genetics to new therapeutic approaches.

Pieces of the Jigsaw Puzzle. Studies of families and, most convincingly, studies on twins prove Dr. Egan’s point that genes in and of themselves are not fate. Identical twins, because they come from the same egg, possess nearly identical genetic material. If genes were destiny, one twin developing the disease would mean the other twin would have 100 percent chance of developing it as well. But several studies have documented that the second twin develops the disease only 40-50 percent of the time.

Genes are thus akin to the foreground in a jigsaw puzzle depicting a landscape. They’re a hugely significant part, and they give clues to what the background and sky might look like, but they do not comprise the whole picture.

Genetic Studies. To study genes, researchers turn their attentions to a structure within the cells that make up our bodies—the cell’s nucleus. Inside each nucleus are 23 strands of genetic material called chromosomes that house the 30-40,000 genes, composed of the well-known molecule called DNA. The genes are the living factories that make protein molecules that control every activity of life.

In the last few years, researchers reached a scientific milestone of incalculable significance when they succeeded in mapping the human genome, that is, they pinpointed the location of every gene in the chromosomes. This historical achievement has touched off a boom in genetic research, including genetic research on severe mental diseases like schizophrenia.

Today’s genetic studies on schizophrenia combine several techniques. They began with so-called linkage analyses of families. Using diagrams similar to those developed by Gregor Mendel in his famous studies of pea plants in the 19^th century, the linkage studies have provided important clues about genetic traits that pass from one generation to another but have been limited in their ability to detect specific genes.

Linkage analysis has been largely supplanted by association studies. Association studies are in some ways much simpler because they compare groups of patients to controls. These groups are much easier to collect than are the large families needed for linkage studies. But association studies do require very large sample sizes. With newly developed techniques, scientists can now quickly sift through mountainous amounts of genetic data to find mutations, abnormal genes, whose malfunctionings likely play a key role in the disease.

Scientists can then factor in findings from the newest imaging techniques, allowing them to see structural and processing abnormalities in the brains of people with schizophrenia.  They also study cognitive behaviors in people with schizophrenia and in control groups of those who don’t have it. When the genetic research, imaging and cognitive studies are combined, they form a coordinated phalanx of research tools that are yielding vital information on schizophrenia.

Narrowing Down the Search for Genes. To narrow down the search for genes involved in schizophrenia, Dr. Egan’s group studies how people behave in the everyday world through simple written tests of cognitive function. One important finding was that people with schizophrenia have impaired short-term memory function. They have trouble holding in their memories things like the phone number given to them by an operator so they have sufficient time to remember and dial it. This kind of short-term memory dysfunction can be an indicator of genetic risk for schizophrenia and a clue to which genes may be acting abnormally because of mutation.

One gene mutation Dr. Egan’s team focuses on is called the COMT variant that affects the metabolism of the brain chemical dopamine, a neurotransmitter. A neurotransmitter is a chemical that instantly transmits signals from one brain cell to the next, a key part of the mechanism by which our brains function. Dopamine is a promising research area because most of the new atypical antipsychotics that successfully treat schizophrenia target the dopamine system in the patient’s brain. Dr. Egan’s group is now studying the effects of a substance that can inhibit the effects of the COMT variant in patients with schizophrenia. It could turn out to be the first genetically based therapeutic drug trial for schizophrenia.

Complicating the matter for researchers is the fact that the effect of the single COMT mutation might be small. But, when the COMT variant acts in concert with the half dozen or so other bad variants of genes associated with schizophrenia, the combined effects can be quite large—and devastating.

“We’re pretty sure that schizophrenia is polygenetic, that is, it’s caused by many genes,” says Dr. Egan. “But we don’t know how many there are, and what they do exactly. Some may have only small effects.

“We need to get more patients and their families to participate so our results are stronger,” he continues. “More complete answers will come as we test larger samples of people.”

Dr. Egan and his team’s meticulous work continues to discover and put in place more pieces to the schizophrenia puzzle. Happily, a discernible whole picture is taking shape, leading inexorably toward a better understanding of schizophrenia and new approaches to treating it.