2001

The risk of having a child with schizophrenia may increase with a father's advancing age, researchers reported yesterday. The researchers, who examined the relationship between the fathers' ages and schizophrenia among 87,907 Israelis born from 1964 through 1976, found that the older the father, the more likely he was to have a child who suffered from schizophrenia, a devastating mental illness.

Men who were 45 through 49, for example, were twice as likely to have offspring with schizophrenia or a related disorder as were men under 25, the researchers found. The overall risk of having a child with the illness, however, remained small.

Other scientists were more skeptical. They noted that confirmation through other studies was needed before such a link could be said to be established, and they cautioned that in the history of schizophrenia research, many apparent associations had eventually proved spurious or impossible to replicate.>If the results of the study hold up to scrutiny, Dr. Malaspina said, "The next question is, `What might explain that finding?'

" One possibility, the researchers argue in their report, is that some cases of schizophrenia area result of genetic abnormalities in sperm cells that become more likely as a man ages. Stem cells in the testicles divide throughout a man's life in a process that leads to the production of sperm. Each cell division carries the chance for copying errors in reproducing the DNA. By the age of 40, research suggests, about 660 such divisions have taken place.

Genetic mutations can also occur from exposure to radiation or chemicals over a man's life. In contrast, the divisions of cells that produce a woman's eggs occur only before birth. A number of physical illnesses and birth defects have been linked to genetic mutations during sperm production in older fathers, including Apert syndrome, a rare congenital deformity of the skull, fingers and toes, and achondroplasia, the most common form of dwarfism. Some cases of schizophrenia, the researchers suggested, might be associated with similar mutations. The illness runs in families, and is known to have a strong genetic component, though efforts to identify the specific gene or genes that predispose a person to schizophrenia have so far been inconclusive. The disease affects 1 of every 100 Americans and is more common in men. Full-blown symptoms often first appear in late adolescence or early adulthood.
In some cases, people who do not have a family history of schizophrenia also develop the illness.

Dr. Malaspina said that the findings of her study "suggest that relevant mutations are there" in such sporadic cases "as well as in familial cases." Dr. James F. Crow, a professor emeritus of genetics at the University of Wisconsin, said, "I think this is very strong evidence for a mutation component to schizophrenia, but it's quite an open question as to how much of a component. But other scientists cautioned that other explanations beside spontaneous genetic mutation could also account for the study's results.For example, said Dr. Ann Pulver, director of the epidemiology and genetics program in psychiatry at Johns Hopkins University, "It may be that the fathers of schizophrenics have unusual characteristics that delay reproduction." "I think this is an interesting contribution to the epidemiological literature, that paternal age may be a risk factor for a subgroup of schizophrenic patients," Dr. Pulver said. "And it may be that advanced paternal age is associated with a mutation. But that is a hypothesis and one would need to test it.

In the study, Dr. Malaspina and her colleagues took advantage of the Jerusalem Perinatal Study, a research archive that includes information about all births in one area of Jerusalem. Records from the study were correlated with those of a national registry of psychiatric illness kept by the Israeli government.

The researchers found that in 1,337 people admitted to psychiatric hospitals before 1998, the fathers' ages were strongly associated with a diagnosis of schizophrenia or a related disorder. The risk of schizophrenia increased steadily with the father's increasing age. Advancing age of the fathers, the investigators reported, accounted for 26 percent of the cases of schizophrenia in the study; for fathers over 50, two out of every three cases of the illness could be attributed to the father's age.

Summary of Research from: Schizophrenia Research; Paternal factors and schizophrenia risk: de novo mutations and imprinting