Older Dads More Likely to Father Kids with Autism

NEW YORK, Sept. 4 -- Men in their 40s are nearly six times more likely than men in their 20s to father children with autism spectrum disorders, according to researchers here and Israel.

An analysis of medical records of more than 300,000 men and women reporting for the draft in Israel revealed that autism spectrum disorders were significantly more prevalent among recruits whose fathers were 40 or older at the time of their birth, found Abraham Reichenberg, Ph.D., of Mount Sinai and colleagues.

There was no association, however, between the mothers' ages at the time of their offspring's birth and autism, the investigators reported in the September issue of the Archives of General Psychiatry.

"Maternal and paternal ages have been associated with other neurodevelopmental disorders and have been considered in some previous studies of autism spectrum disorders," the authors wrote. "Advancing maternal age increases the risk of chromosomal abnormalities, such as Down's syndrome, and has been associated with the risk of brain damage during pregnancy, dyslexia, and mental retardation of unknown cause."

Similarly, advanced paternal age has been associated with several congenital disorders, including Apert's syndrome, a congenital disorder characterized by craniosynostosis, midface hypoplasia, and fusion of appendages and bony structures of the hands and feet. The condition has been associated with de novo germline mutations in older fathers, the authors noted.

"Therefore, one of the reasons for examining the relationship between paternal age and autism spectrum disorders is that it may provide clues to the biological pathways leading to autism spectrum disorders," they wrote.

To test this assumption, they conducted an historical population-based cohort study using data from the Israeli draft board medical registry. They looked at a cohort of inductees born during six consecutives years in the 1980s.

Data on the fathers' age at birth were available for 318,506 of the recruits, and data on the mothers' age at birth were available for 132,271 out of the larger sample.

The authors performed their primary analysis using the smaller dataset containing information about both parents, and they used the larger dataset containing information only on paternal age at birth for sensitivity analyses.

They used ICD-10 coding to identify from the draft board medical registry members of the cohort with an autism spectrum disorder.

They identified a total of 208 recruits with an autism spectrum disorder in the larger cohort (paternal data only) yielding a prevalence rate of 6.5 per 10,000, and 110 cases of autism spectrum disorders, for a prevalence rate of 8.3 cases per 10,000, among the cohort for whom complete parental data were available.

The investigators found that there was "a significant monotonic association between advancing paternal age and risk of autism spectrum disorders."

After controlling for year of birth, socioeconomic status, and maternal age, the adjusted odds for autism spectrum disorders among offspring of men age 40, compared to children of men younger than 30, was 5.75 (95% confidence interval, 2.65-12.46; P<0.001).

In contrast, after adjusting for paternal age there was no significant association between the mother's age and risk of autism spectrum disorders. The sensitivity analyses ensured that the findings were not biased because of missing data on maternal age, the authors wrote.

"Among the possible mechanisms for an effect of paternal age on autism spectrum disorders risk are point mutations or structural chromosomal aberrations in the father's germline, or imprinting, in which an allele inherited from the father suppresses the expression of the mother's allele and determines the expression of a particular gene," the authors wrote.

"Although our understanding of genetic imprinting is nascent, it merits consideration in autism," they added. "Imprinted genes play a key role in brain development, investigations of Turner's syndrome suggest a role for imprinted genes in language development and social functioning, and parent-of-origin effects have been reported in Angelman's syndrome and in at least some autism studies."

They noted that most people in the cohort were determined to have autism, and that their finding of a paternal age effect may not apply to other autism spectrum disorders, such as Asperger's syndrome.

They acknowledged that the statistical power of their study was limited by the low number of autism spectrum disorders cases. However, the effect was large enough to yield narrow confidence intervals and statistical significance, and was confirmed by sensitivity analyses.