UW News

August 17, 2006

Of famine, folate and schizophrenia: Link studied between genetic mutations and lack of micronutrients

When doctors and scientists look for the underlying causes of a disease or a condition, they usually put everyone with the ailment together in one big group and see what they have in common.

People with lung cancer or emphysema? Many of those stricken were also smokers.

A population suffering an outbreak of a bacterial infection? Maybe the area’s water supply has become infected.

Those common factors can often help researchers link a cause with a disease. But in the case of schizophrenia, which is inherited but tends to occur sporadically in families, scientists have struggled to find an underlying cause. They have found an intriguing link between the mental disorder and one possible cause: famine.

In populations living through famine conditions, children who were in the womb during the famine are at a nearly two-fold higher risk of developing schizophrenia than in the general population.

Though famine victims make up a tiny fraction of all those who suffer from schizophrenia, that link may help researchers better understand the genetic basis of the debilitating disorder, and could shed light on how many conditions are carried on in our genetic code.

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 Dr. Jack McClellan, UW associate professor of psychiatry and medical director of the Child Study and Treatment Center in Tacoma. “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.

The important finding here isn’t so much that famine can cause higher risk of schizophrenia, since so many more people develop the condition without any connection to famine. What is important is that it seems to be new genetic mutations cropping up throughout the population that cause schizophrenia, rather than a single gene (or handful of genes) from distant ancestors causing all cases of the mental disorder.

McClellan and two fellow researchers, 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, urged further research in this area in the Aug. 2 issue of JAMA, a journal published by the American Medical Association. They argue that schizophrenia is the latest in a string of disorders that challenges the conventional wisdom on inherited conditions — 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.”

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.