ABOUT ONE OF EVERY FOUR AMERICANS SUFFERS FROM A DIAGNOSABLE MENTAL DISORDER, ACCORDING TO THE NATIONAL INSTITUTE OF MENTAL HEALTH. ABOUT 6 PERCENT OF AMERICANS STRUGGLE WITH SERIOUS MENTAL ILLNESS. RESEARCH HAS SHOWN THAT MENTAL ILLNESS ACCOUNTS FOR ABOUT 15 PERCENT OF THE TOTAL BURDEN OF DISEASE ON OUR SOCIETY, MORE THAN ALL CANCERS COMBINED.

Most major psychiatric illnesses, such as schizophrenia, autism, and bipolar disorder, are multifactorial disorders that can’t be traced to any single “schizophrenia gene” or “autism gene.” Understanding the complex combination of genetic and environmental factors that interact to produce mental illness is the primary challenge of contemporary psychiatry and the top priority of Columbia’s integrated psychiatry program, says Jeffrey Lieberman, M.D., chairman of the Department of Psychiatry at P&S, director of the New York State Psychiatric Institute, and director of the joint Columbia and NYSPI Lieber Center for Schizophrenia Research. “Unfortunately, psychiatry has so far identified very few of the genes implicated in major mental illnesses such as schizophrenia. At Columbia, we are currently using a number of innovative methods and state-of-the-art technologies to pursue promising avenues of genetic discovery.”

Heat map illustrating the distribution of pair-wise linkage disequilibrium — the chance that any two variants in a gene or neighboring genes are co-inherited — in the 22q11 schizophrenia susceptibility locus. Image courtesy of Maria Karayiorgou.

     Schizophrenia is one of the most devastating of psychiatric disorders and a major focus of research and treatment at Columbia. The delusions, hallucinations, and other debilitating symptoms of schizophrenia shatter not only the life of the person with the illness, but also the lives of family members. Some 40 percent of people with schizophrenia have substance abuse problems, and their average life expectancy is 10 to 12 years shorter than normal. In fact, schizophrenia’s mortality rate is higher than that of some cardiovascular diseases and some cancers, with 15 percent to 20 percent of those whose illness is inadequately treated attempting suicide.
     This year at Columbia, Nobel laureate Eric Kandel brought scientists one vital step closer to understanding the genetic underpinnings of schizophrenia by creating the first genetic mouse model of schizophrenia. Most scientists believe that hyperactivity in the brain’s dopamine system plays a key role in the development of schizophrenia. So Dr. Kandel and his colleagues developed genetically altered mice that overexpress dopamine in the striatum, a part of the brain that affects cognitive function in people with schizophrenia. And indeed, the mice showed difficulty in completing maze tasks and otherwise demonstrated the same kind of working-memory deficits that plague people with schizophrenia, an effect Dr. Kandel was not able to reverse merely by using an antibiotic to lower dopamine production. This finding, he says, suggests that the detrimental effects of excessive dopamine production may happen earlier on in neurodevelopment; antipsychotic drugs prescribed after the disease’s symptoms set in may be too late to reverse the abnormalities at the core of schizophrenia.
Of course, mice are not humans, and the neural circuitry involved in human schizophrenia is far more complex than that found in a mouse. But Dr. Kandel’s schizophrenic mouse offers scientists the first opportunity to study the disease in an animal model and experimentally test theories about the development of the disease and potential treatments.
     Dr. Kandel’s discoveries are complemented by the recent arrival of another world-class scientist with expertise in the genetics of schizophrenia: Maria Karayiorgou, M.D., formerly of Rockefeller University, who joined the faculty in 2006. Dr. Karayiorgou studies schizophrenia using “founder populations” – a group of people descended from a limited number of common ancestors, who have not intermarried much with outside groups whether because of geography, language, religion, or other factors. Because of their homogeneity, these founder populations are ideal for the study of genetics and inheritance. Dr. Karayiorgou is working with a founder population among the Afrikaners of South Africa to identify candidate genes that lead to vulnerability to schizophrenia, by creating one of the first genome-wide association scans ever created for a complex disease.

Maria Karayiorgou, M.D., found that a missing section of chromosome 22 greatly increases risk to schizophrenia. Her research building on that finding has contributed to recent efforts to identify disease genes. Dr. Karayiorgou also studies South Africa’s Afrikaners, a homogeneous group that grew from a few thousand Dutch immigrants, to identify additional susceptibility genes.

     “Dr. Karayiorgou has already made some very important discoveries,” says Dr. Lieberman. One of these discoveries explains why some people have a drastically increased risk for schizophrenia. For most of the population, the schizophrenia rate is about 1 percent. However, people born without a small section of chromosome 22, called 22q11, face nearly a one in three risk of developing schizophrenia. This deletion is the disease’s greatest known risk factor, but why? Last year, while still at Rockefeller, Dr. Karayiorgou and Joseph Gogos, M.D., Ph.D., Columbia assistant professor of physiology and cellular biophysics, identified an important interaction between two genes in a section of chromosome 22 that may explain the importance of this deletion. They found that mice deficient in a particular gene called PRODH show some symptoms similar to schizophrenia, and another gene, COMT, can compensate for the lack of PRODH. It turns out that both of these genes are located in that same 22q11 region of chromosome 22, so patients with the deletion cannot compensate for low levels of PRODH with increased levels of COMT, since one copy of that gene is missing as well. Their research was reported in the journal Nature Neuroscience.
     Other psychiatric disorders, such as posttraumatic stress syndrome, anxiety disorder, and phobias, also may have genetics roots – and genetic possibilities for treatment. That’s the intriguing possibility suggested by new research from Dr. Kandel. “All animals, including people, have instinctive fear, a built-in response to obvious danger signals. If a ferocious dog jumps on you, you don’t have to learn to jump away,” he says. “It’s built into the genome.” But the learned fear that can impair the lives of people who have suffered great trauma is governed by a different pathway in the brain’s amygdalae, areas that play a key role in the processing and memory of emotional reactions.
     Using a mouse model, Dr. Kandel has found that a protein called stathmin is essential to both instinctive and learned fear. By suppressing the stathmin gene, researchers created a “fearless” mouse, one with virtually no learned or instinctive fear. They also were able to selectively modify the fear pathways in another mouse, leaving the instinctive fear behaviors unchanged while altering learned fear. These findings, published in the journal Cell, hold great promise for people with phobias, posttraumatic stress, and chronic anxiety disorders. “These are all excessive responses to learned fear,” says Dr. Kandel. “This suggests potential new approaches for therapies designed to treat these conditions.”

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