Fathers over 40 'much more likely to have autistic children'

Also rate high in fathers over 30 compared to younger men.



05/09/2006

Fathers over 40 'much more likely to have autistic children'


LONDON, UK: Children with fathers over the age of 40 have a significantly increased risk of having autism, a study has concluded.

The team of British and American US experts said that children born to men older than 40 had a six times higher risk than those born to men under 30.

They said the study, published in the September 2006 edition of the Archives of General Psychiatry, was further proof that men also had "biological clocks."

One British expert said the study could be important in understanding the genetic mechanisms underlying autism.

Autism and related conditions, known as autism spectrum disorders, have become increasingly common, affecting 50 in every 10,000 children as compared with five in 10,000 two decades ago.

Increased awareness and changes in the way the disorders are diagnosed are thought to play a major role in the increase, but the researchers say it may also be linked to other changing factors.

Older parental age has previously been linked to abnormalities in the brain development of children.

The researchers, from the Institute of Psychiatry at King's College London and Mount Sinai School of Medicine, New York, looked at data on 132,271 Jewish children born in Israel during the 1980s. All men, and three-quarters of women born in these years, were assessed by the draft board at the age of 17 for eligibility to serve in the Israeli military, during which time any disorders were recorded. Among them, 110 had been diagnosed earlier with autism or related disorders, including Asperger's syndrome. The researchers said their results may not apply to Asperger's or other autism-like disorders.

Among those whose fathers were between 15 and 29 when they were born, the rate of autism was six in every 10,000, rising to nine in every 10,000 when fathers were aged 30 to 39 (1.6 times higher). In the group whose fathers were aged 40 to 49, the rate rose to 32 in 10,000 (5.75 times higher).

The rate appeared to be even higher when fathers were aged over 50, but the researchers said the sample size was very small. The mother's age did not appear to influence the chances that a child would have autism.

The researchers suggest there may be a genetic fault which is more common with age. This might be spontaneous mutations in sperm-producing cells or alterations in genetic "imprinting," which affects gene expression.

The team, led by Dr Abraham Reichenberg from the Mount Sinai School of Medicine, said: "It is important to keep in mind that age at paternity is influenced by the socio-cultural environment and varies across societies and over time. In a given population, a change in the socio-cultural 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 of autism."

He added: "Although further work is necessary to confirm this interpretation, we believe that our study provides the first convincing evidence that advanced paternal age is a risk factor for autism spectrum disorder."

Professor Simon Baron-Cohen, director of the Autism Research Centre in Cambridge, UK, said: "The finding of a significant association with advancing paternal age is one that should be straightforward to test in other samples, to see if this result from a purely Israeli sample generalises to other populations. If confirmed, it could have important implications for the genetic mechanisms underlying autism."

Other autism experts called the study intriguing, but not definitive, and the authors said the results needed to be tested in a broader population to see if similar findings would occur in other ethnic groups.

This is not the first time that fathers' age has been implicated in autism, but the new research stood out because "it's a strong effect in a carefully designed study," said Dr Edwin Cook, an autism researcher at University of Illinois-Chicago who was not involved in the study.

"Maternal and paternal ages have been associated with other neurodevelopmental disorders and have been considered in some previous studies of autism spectrum disorders," the study 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 characterised 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.

"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.

Although the fact that all the children were Jewish was a limitation of the study, Dr Reichenberg did not believe it affected the results. More research was needed to see if the findings were replicated across other racial and ethnic backgrounds.

"It's a very interesting, strong study," said Dr Fred Volkmar, an autism researcher at Yale University who was not involved in the research.

Dr Volkmar said the study was consistent with a prevailing theory that genes are a cause of autism, but he said the results needed to be tested to prove that the fathers' age was a culprit. For example, the study lacked information on whether the fathers themselves had autism.

The risk of birth abnormalities such as spina bifida increases sharply with advancing age in mothers but is popularly thought to be unaffected by the age of the father. However, experts say that this may be because fathers have not been studied as closely as mothers.

"A lot of research has focused on mothers, and fathers have not had the same attention. It may be problem is the same [in both sexes] but the research has not been done," said a spokesperson for the Progress Educational Trust, a charity supporting research into fertility.

(Sources: BBC News Online, Associated Press, MedPage Today, The Times, The Independent, September 5, 2006)