Genetic mutations may be responsible for schizophrenia

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 Journal of the American Medical Association.

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."