The higher risk of schizophrenia among offspring of expectant mothers living through famine could help us understand the genetic basis for that debilitating mental disorder, a group of researchers argue in a commentary piece in the Aug. 2 issue of JAMA. The finding also supports a theory of medical genetics in which diseases and conditions can be caused by hundreds of different genetic mutations in any number of human genes.

Epidemiologists have studied two major famines in the 20th century: the Dutch Hunger Winter of 1944-45, which was brought about by the Nazi occupation in World War II; and the Chinese famine in 1959-61, a consequence of the failed Great Leap Forward. During both famines, birth rates dropped precipitously. In addition, among children born to women who were pregnant during the famine, the incidence of schizophrenia increased two-fold.

The expectant mothers were not receiving enough folate and other vital micronutrients during the famine, researchers believe, and that deficiency caused new genetic mutations to appear at exceptionally high rates. New mutations in genes related to brain function could lead to development of schizophrenia

"Folate has a major role in genetic processes -- gene transcription and regulation, DNA replication, and the repair of damaged genetic information," explained co-author Dr. Jack McClellan, an associate professor of psychiatry at the University of Washington and medical director of the Child Study and Treatment Center in Tacoma, Wash. "If folate is missing from a mother's diet, that could lead to genetic mutations in the developing fetus."

Nearly three-quarters of the human body's 20,000 or so genes are involved in the development or functioning of the brain in some way, and about one-fourth are specifically brain-related genes -- leaving many possible locations where new genetic mutations would affect the brain. Since schizophrenia has its genesis in the development and distribution of neurons, McClellan said, the areas of the genome related to those processes are probably where researchers will find disease-related mutations.

In addition to urging future research in this area, McClellan and his co-authors, Dr. Ezra Susser of Columbia University and Dr. Mary-Claire King, the American Cancer Society Professor of Medical Genetics and Genome Sciences at the UW, argue that schizophrenia is the latest in a string of disorders showing the nature of inheritance of genetic conditions. The conventional wisdom on psychiatric disorders is that most cases are caused by a handful of common genetic mutations that occur in a small number of genes.

"The problem with that model is that it doesn't correspond to clinical experience," said King. "Studies of families with many complex diseases, like breast cancer, epilepsy, or inherited hearing loss, indicate that many different genetic mutations in many different genes can lead to each disease."

Researchers jokingly refer to this hypothesis as the Anna Karenina model of medical genetics -- each unhealthy family is unhealthy in its own way.

This alterative model of genetics helps explain other aspects of schizophrenia as well. In nearly all populations, the disease has a fairly stable rate of incidence. But in populations with maternal famine, that rate increases significantly. If there are many different possible mutations that could cause schizophrenia, and the number of mutations in a population goes up (due to malnutrition, for example), then one would expect the rate of the disease to rise, as it did during the two famine events.

In addition, schizophrenia can affect the rate of reproduction in people with the condition -- they often have difficulty developing and maintaining relationships with others, so tend to have smaller families and fewer children than other people. If only a small number of common genetic mutations were responsible for schizophrenia, scientists would expect them to become less and less common over time, as people with the condition had fewer children who would carry on those mutations. Instead, the risk of schizophrenia has stayed at about the same level, suggesting that new genetic mutations may crop up periodically to cause the illness anew.

Schizophrenia does run in families, but most people with the condition do not have close relatives with schizophrenia. For many schizophrenia patients, their illness seems to come from out of the blue. This pattern also suggests that new, different mutations appear in different families, McClellan said, and may continue for a few generations before dying out. That could make it hard to determine which genetic mutations cause the disease.

"Normally, if you're looking for what causes an illness, you gather everyone with that illness together and look for mutations they share," said McClellan. "That may be why it has been so hard to find the genetic basis for schizophrenia. The cause may be different from one case to another."

The researchers hope to use genomics tools to learn more about the genetic mutations that may be responsible for schizophrenia. They have been invited by collaborators in China to study survivors of the Chinese famine of 1959-61.

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