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Combining register data with genetic analyses for research on mental illness
By Lone Frank

Since 1969, the Danes have kept a central register of all patients who have come into contact with the country's socialized psychiatric health care system. Although meant as a tool for planners and administrators, these records have turned out to be a crucial resource for scientists searching for the causes of mental illness. Over the past three decades, researchers have used the patient data to identify a host of environmental risk factors, but a Danish team is now ready to also look at genes. By combining the register data with the power of modern genetic technologies, they hope to shed light on the complex interactions between nature and nurture that result in disorders such as schizophrenia.

The register data are very basic and tell a simple tale of the patient's diagnosis, his treatment and the length of each hospital stay. However, this can become very revealing when correlated with information from other registers, made possible through the Danish Civil Registration System. In Denmark, every resident is assigned a personal identification number (CPR) at birth, and all through life this number is registered on encounters with most private and public systems from kindergarten to library cards and medical records.

first scientific evidence of the genetic component of schizophrenia

"By tracking the CPR number of psychiatric patients in other registers we can extract otherwise hidden information about statistical risk factors that are connected to a given psychiatric disorder. But it is important to understand that each person's identity is masked to the researchers, and that all studies are approved by the authorities," says Dr. Preben Bo Mortensen, who is a psychiatric epidemiologist at the Institute for Basic Psychiatric Research at Aarhus University Hospital. Through his extensive work with the Danish Psychiatric Central Register, Dr. Mortensen has placed himself at the center of a wide-reaching international network of research projects drawing on the Danish patient data. One of his primary interests is schizophrenia, which many regard as the most serious psychiatric disorder. Its causes are still largely unknown, but as Dr. Mortensen explains, "there seems to be a strong genetic component and most experts agree that a number of non-genetic factors must be present to cause schizophrenia to break out."

In fact, the first scientific evidence of the genetic component in schizophrenia was provided by the Danish Psychiatric Central Register. In the 1950s, Denmark's Dr. Fini Schulsinger and his American colleague, Dr. Seymour Kety, analyzed data of a group of Danes diagnosed with the disease, all of whom were adopted. With the study's results they were able to poke a large hole in the belief that schizophrenia is caused by traumatic childhood experiences.

Since then, most register studies have focused on identifying the various environmental factors that form the non-genetic part of the equation. Over the years, Dr. Mortensen has lead or collaborated on studies that have pointed out how circumstances such as premature birth, low birth weight, complications at birth, and severe head trauma during childhood increase a person's likelihood of developing schizophrenia later in life. Surprisingly, even the time and place of birth play a role. In one of the world's largest epidemiological studies of multiple risk factors in schizophrenia, recently published in The New England Journal of Medicine, Dr. Mortensen and his colleagues showed that being born during the winter months or being born in urban rather than rural areas makes a person more likely to develop schizophrenia. However, the study also firmly underscored that the strongest single predictor of schizophrenia is a family history of the disease.

"Our understanding of the environmental factors can help lower the incidence of the disease in the population as a whole through preventive measures. This could be by providing children with bike helmets to prevent head trauma or preventing low birth weight by advising women not to smoke during pregnancy," says Dr. Mortensen. But he stresses that in order to develop better treatments for schizophrenia it is crucial to gain an understanding of its biological mechanisms. That means identifying the genes that make some people more susceptible to the disease and elucidating their function in the brain. Dr. Mortensen now plans to join forces with experts in molecular biology and genetics, and for the first time he will directly involve biological material in his studies.

DNA from blood samples will be used to look at genetic markers

Within the coming months the Danish team will start collecting blood samples from approximately one thousand patients newly diagnosed with either schizophrenia or bi-polar disorder as well as from their close relatives. Concurrently, the researchers will be gathering extensive information relating to the patients' living conditions by asking questions concerning everything from breast feeding to family pets.

While the answers to all these questions will provide a catalogue of possible environmental risk factors, the DNA from blood samples will be used to look at genetic markers. Dr. Mortensen calls the combination "a very strong tool not only for finding the involved genes but also for clarifying how interactions between genes and other risk factors cause disease." Initially, the researchers will investigate a few genetic markers that are already under suspicion for being involved in schizophrenia and bi-polar disorder, but as the list grows, more studies will be conducted. And in order to make optimal use of the valuable resource, the Danish researchers intend to keep their gold mine open to others. Dr. Mortensen stresses that colleagues with ideas about candidate schizophrenia genes will be welcome to suggest and collaborate on projects using the register data and DNA samples.

But will patients and their families also collaborate and volunteer to give the researchers not only blood but also access to very personal information? Dr. Mortensen has little doubt. "It is our general experience that people who know the devastating effects of serious mental illness are very open to participating in scientific studies. They want to help identify the underlying causes that will make it possible to create better treatments."

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