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Jewish World Review April 13, 2001 / 20 Nissan, 5761

Lee Bowman

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Consumer Reports

Older fathers more likely to sire schizophrenic kids -- OLDER men are much more likely to father children with schizophrenia, with men in their 40s twice as likely to have offspring with the illness than men under age 25.

Men in their 50s or older are at three times the risk of having a child with the disorder, according to research published Friday in the Archives of General Psychiatry.

"A man has a biological clock, too. They should be aware of the risks when they do their family planning," said Dr. Dolores Malaspina, lead author of the report and an associate professor of psychiatry at Columbia University College of Physicians and Surgeons in New York.

The new study, coupled with earlier research, bolsters the theory that as men age, sperm cells can accumulate mutations that are passed to their offspring.

"I would guess that our study is just the tip of the iceberg," said Dr. Susan Harlap, a research professor of epidemiology at New York University School of Medicine and a co-author. "Eventually it would seem that the father's sperm is going to turn out to be just as important (to genetic defects) as the mother's egg."

The study marks the first time that advancing paternal age has been linked to a brain disorder as opposed to more apparent, but rare, physical deformities or illnesses such as nerve and prostate cancer.

Women's eggs may also develop chromosomal abnormalities, but these typically involve larger changes that are easier to catch through genetic tests. Sperm mutations tend to occur at a single point on a strand of DNA.

Schizophrenia is thought to result from a still poorly-understood combination of genetic flaws and environmental factors. It is marked by delusions or hallucinations, disorganized or incoherent speech and severely disorganized or catatonic behavior, and is most often diagnosed between the late teens and early 30s.

The new study, backed by the National Institute of Mental Health and the Mathers Foundation, doesn't identify any specific gene defects but does help explain some aspects of how schizophrenia is both so persistent and widespread.

The disorder is enduring in human populations over time, even though individuals with schizophrenia are less likely to reproduce due to the social deficits common in the disease. Thus, over time, evolution normally would make the disease less prevalent, unless new cases continue to arise due to mutations.

Secondly, if environment were a major cause of the disease, than incidence would vary with geography. Instead, about 1 percent of the individuals in every human population around the globe has the disorder, including about 2.2 million Americans.

The researchers suggest that new mutations are introduced to the disease-causing genes each time cells divide. In older men, the cells that eventually become sperm have already divided several hundred times. Each of the divisions offers a new chance for random mutations to occur in one or more of the genes responsible for schizophrenia.

By contrast, a woman's egg cells divide only 24 times, and almost all the divisions occur before she's born, making it less likely that mutations will occur.

The study is based on a registry of nearly 88,000 people born in Jerusalem between 1964 and 1976 and a second database of people with psychiatric diseases maintained by Israel's Ministry of Health. The U.S. researchers were given access to a set of the records stripped of names and other identifying information.

The scientists found that only schizophrenia has a strong connection to paternal age at birth. Overall, they estimate that 26.6 percent of schizophrenia cases were attributable to the father's age. For fathers over age 50, however, two out of three cases among their children were linked to their age at conception.

Malaspina noted that the study also found that risk of schizophrenia decreases somewhat as the length of the parents' marriage increases, but still falls short of canceling out the effect of the father's age.

Harlap said the new findings should not rule out older men fathering children. "I don't think older men should disqualify themselves from becoming parents," he said. "Our study suggests that a man's progeny are going to be healthiest if he has his children during his early 20s, but we know that many men aren't ready for marriage and parenthood at that age.

"A man may want to wait until he is mature enough and economically stable enough to have children, even though there are health risks in having children at an older age."

Malaspina added that the new findings point schizophrenia researchers away from environmental factors and more toward gene-environmental interactions and modifications made to genes in the course of aging.

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