Paternal Age, de Novo Mutations and Autism Risk

Ted Schettler, MD, MPH
Science Director

A recent study of paternal age, de novo DNA mutations, and autism risk in Iceland, published in the journal Nature, has received considerable attention. The authors of the study found more de novo DNA mutations in children with autism and those mutations were largely traced to fathers rather than mothers. Increasing numbers of mutations were also associated with increasing paternal age. The authors wondered if recent increases in autism were largely attributable to the increasing age of fathers.

The New Yorker said, “What was surprising was how that news, which one of the study’s lead authors described as “sort of a little bit of our side story,” obscured the implications of the paper’s main findings—namely, that the genetic health of the species is now facing a serious threat.” Read more.  Important as this is, most reports have failed to comment on another observation in the paper.  The authors said this:

“There has been a recent transition of Icelanders from a rural agricultural to an urban industrial way of life, which engendered a rapid and sequential drop in the average age of fathers at conception from 34.9 years in 1900 to 27.9 years in 1980, followed by an equally swift climb back to 33.0 years in 2011, primarily owing to the effect of higher education and the increased use of contraception. On the basis of the fitted linear model, whereas individuals born in 1900 carried on average 73.7 de novo mutations, those born in 1980 carried on average only 59.7 such mutations (a decrease of 19.1%), and the mutational load of individuals born in 2011 has increased by 17.2% to 69.9. Demographic change of this kind and magnitude is not unique to Iceland, and it raises the question of whether the reported increase in ASD diagnosis lately is at least partially due to an increase in the average age of fathers at conception.”

This means that If increased paternal age alone explains much of the autism risk through increasing numbers of DNA mutations, then one would expect autism prevalence in Iceland in 1900 to have been somewhat similar to what it is today, since average paternal age at conception was similar in 1900 and 2011.  This seems unlikely although we’ll never know since autism wasn’t described until the 1940s.

But the authors of the study also said, “even though factors other than father’s age do not seem to contribute substantially to the mutation rate diversity in our data, it does not mean that hazardous environmental conditions could not cause a meaningful increase in mutation rate. Rather, the results indicate that, to estimate such an effect for a specific incident, it is crucial to take the father’s age into account.”

What might those environmental conditions be? Vitamin D, for example, plays an important role in DNA repair.  It would be useful to know how vitamin D status among Icelanders may have changed since 1900. It looks as if low or inadequate levels of vitamin D are common in Iceland today. See “Relationships between vitamin D status and cardio-metabolic risk factors in young European adults.” Could levels of vitamin D have been higher in Icelanders in 1900? What other environmental factors may be contributing to the de novo mutations seen with advancing paternal age?

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One thought on “Paternal Age, de Novo Mutations and Autism Risk

  1. Thank you for this post. As an advanced age father (55) of an autistic child (8), I often wonder what made my boy autistic. Could the fact that he, his mother and I live near the intersection of two of the busiest freeways in Los Angeles have something to do with it? What have my genes been exposed to (or not exposed to) for 55 years that may have contributed to my son’s condition? Only time and nuanced thinking will tell.

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