Older men are at higher risk of fathering autistic children than are younger men, results of a large cohort study suggest.
After a man reaches his 20s, the risk of fathering an autistic boy or girl more than doubles with every 10-year increase in his age. This increase is independent of other factors such as the mother's age and the family's socioeconomic status, reported Abraham Reichenberg, Ph.D., of Mount Sinai School of Medicine, New York, and his associates.
Older paternal age at the birth of offspring is associated with several congenital disorders, and it also has been linked to schizophrenia and to decreased intellectual capacity. Previous studies examining a possible link between paternal age and autism risk have produced mixed results, but “few have systematically examined this association in rigorous designs that included adjustment for maternal age,” Dr. Reichenberg and his associates said (Arch. Gen. Psychiatry 2006;63:1026–32).
They conducted a very large population-based cohort study “specifically designed for a rigorous test of the hypothesis that advancing paternal age is associated with increased risk of ASD [autism spectrum disorder] in offspring.”
The investigators used data collected on a cohort of 378,891 Israelis born during a consecutive 6-year period in the 1980s and evaluated at age 17 by the Israeli draft board, which determines intellectual, medical, and psychiatric eligibility for the country's compulsory military service. The birth dates of both mothers and fathers were available in 132,271 members of the cohort.
The draft board also reviews detailed medical records on all Israelis with developmental disabilities, including the virtually 100% of children and adolescents diagnosed with ASDs who receive universal health care and other services through government agencies.
The overall prevalence of autism spectrum disorders in this cohort was 8.4 cases per 10,000 persons.
The risk of ASDs increased significantly with advancing paternal age and was “especially strong” in offspring of the oldest men. Compared with fathers in their late teens or twenties, the risk of fathering an autistic child was 1.6 times higher among men in their 30s, 5.7 times higher among men in their 40s, and 9.4 times higher among men aged 50 and older, Dr. Reichenberg and his associates said.
The increase in risk persisted after the data were adjusted to account for maternal age, socioeconomic status, and other potentially confounding factors. Risk was increased for both male and female offspring.
Although all ASDs were included in this study, almost all the subjects in this cohort had autism itself. The study findings therefore may not necessarily be generalizable to the other disorders in the spectrum, such as Asperger's syndrome and Rett syndrome. “The relationship of paternal age to these disorders should be specifically examined in more contemporary cohorts,” the researchers noted.
One possible mechanism for this effect of paternal age is mutagenesis. Spontaneous mutations–either point mutations or structural chromosomal anomalies–might arise and accumulate in successive generations of sperm-producing cells.
Another possible mechanism is imprinting, a form of gene regulation in which the gene of only one parental allele is expressed and the other one is silenced. It is possible that for paternally imprinted genes, biological processes may be impaired as the father ages. Imprinted genes are known to play a key role in brain development, they added.
“These hypothesized mechanisms for paternal age effects on risk of ASD are genetic. It is important to keep in mind, however, that age at paternity is influenced by the sociocultural environment and varies across societies and over time.
“In a given population, a change in the sociocultural environment could produce a change in paternal age at birth. In theory, it could thereby lead to a change in the incidence of genetic causes autism,” Dr. Reichenberg and his associates said.
One study limitation was that no information was available on possible autistic traits in the subjects' parents. It's possible that if fathers had some traits related to the autism phenotype, especially social deficits, these may have contributed to their older age at marriage and fatherhood.