Advancing paternal age accounts for as many as one in four schizophrenia cases, said Dolores Malaspina, M.D., lead author of the study. Dr. Malaspina is associate professor of clinical psychiatry at the Columbia University College of Physicians & Surgeons and head of the Laboratory of Clinical Neurobiology at the New York State Psychiatric Institute's Medical Genetics Division.

The findings complement other studies that show "a man has a biological clock, too," Dr. Malaspina said. "Men should be aware of the risks when they do their family planning."

The research supports the hypothesis that as the fathers age, sperm cells can accumulate mutations that are passed to offspring, say the study's authors. The findings are published in the April issue of the journal Archives of General Psychiatry.

A child's risk of developing schizophrenia rises dramatically and steadily as the age of the father increases, according to the study, conducted in collaboration with New York University School of Medicine and the Israel Ministry of Health.

The findings suggest that men between the ages of 45 and 49 are twice as likely than those under age 25 to have children with the devastating mental illness. Men aged 50 or older, furthermore, appear to be at three times that risk.

Schizophrenia is believed to result from an as-yet poorly understood mix of genetic and environmental factors. Several genes may be involved.

The new findings don't identify the genetic culprits but do help explain several longstanding mysteries about schizophrenia's epidemiology.

First, the illness is remarkably persistent in human populations over time. This is a puzzle because individuals with schizophrenia are less likely to mate and reproduce, presumably because of the social deficits in the illness, so evolution would normally tend to decrease the proportion of individuals with the disease, unless new cases kept arising through new mutations.

A related fact is that schizophrenia's incidence is strikingly consistent across human populations -- about one percent of individuals in every population have schizophrenia. If environmental factors accounted for most of the disease, the incidence would vary in different areas.

The new findings may help explain both puzzles by showing how, in each generation, new genetic mutations replenish the genes for schizophrenia and keep the incidence stable across populations.

This may also explain why a growing number of genetic diseases are being linked to advancing parental age. As men age, their sperm continue to reproduce through division. Each successive division introduces a slight risk of error in the genetic material of the new sperm, which is passed on to the children.

In women, by contrast, almost all of the divisions in eggs occur before their birth and the eggs don't continue to divide as they age.

"I would guess that our study is just the tip of the iceberg," said Susan Harlap, M.D., research professor of epidemiology in the Department of Obstetrics and Gynecology at New York University School of Medicine and an author of the new study. "Eventually it would seem that the father's sperm is going to turn out to be just as important as the mother's egg."

Women's eggs may also develop chromosomal abnormalities, but these typically involve larger chromosomal changes and thus are easier to catch through genetic tests. Sperm mutations are so-called "single-point" mutations, which are tiny and almost impossible to catch without knowing in advance what mutations to look for.

The new study marks the first time advancing paternal age has been linked to a psychiatric rather than a physical illness, Dr. Malaspina said. Conditions previously linked to advancing paternal age include prostate cancer, nervous system cancer, neurofibromatosis (fleshy growths of abnormal nerve tissue), the most common type of dwarfism, Apert syndrome (malformation of the skulls, hands and feet), and Marfan syndrome, which involves defects of the eyes, bones, heart and blood vessels.

The schizophrenia study was conducted by reviewing the records of 87,907 people born in Jerusalem between 1964 and 1976 and linking the records to those of the Israel Psychiatric Registry within the Israeli Ministry of Health.

Interestingly, Dr. Malaspina added, the study also found that the risk of schizophrenia decreases somewhat as the length of the parents' marriage increases. This correlation works opposite to, but doesn't cancel the effect of, advancing paternal age, Dr. Malaspina said.

Dr. Malaspina added that the new findings on paternal age should help redirect research strategies for identifying schizophrenia's causes. First, researchers may want to focus less on independent environmental causes, she explained. These factors are still important, but researchers should probably focus on gene-environment interactions rather than the environment as a sole culprit, she said.

Second, researchers can focus on identifying gene modifications in cases of advanced paternal age, she continued. Columbia researchers are beginning this work, starting with mice. "We're going to look for changes in gene expression (activation) in mice with older parents."

The study was funded by the National Institute of Mental Health and the G. Harold and Leila Y. Mathers Foundation. - By Carolyn Conway Hoare

[Contact: Carolyn Conway Hoare]

13-Apr-2001