Paternal Age Ups Autism, Schizophrenia Risk in Offspring

Pam Harrison

August 22, 2012

August 22, 2012 — Increasing paternal age at the time of conception increases the risk of de novo mutations appearing in the sperm that, when passed on to the offspring, increase the child's risk for both schizophrenia and autism spectrum disorder (ASD), new research shows.

A large genetic sequencing project carried out by Icelandic investigators showed that the probability of a 40-year-old father having a child with either schizophrenia or ASD is approximately twice that of a 20-year-old father, owing to an important increase in the number of de novo mutations in the sperm due to increasing age.

"De novo mutations occur in the eggs or sperm with germ cell proliferation, and they are mutations that occur only in the eggs or sperm. The mother or father do not have the same mutations themselves," investigator Kári Stefánsson, MD, Dr Med, chief executive officer, deCODE Genetics, Reykjavik, Iceland, told Medscape Medical News.

The study was published in the August 23rd issue of Nature.

"Striking" Finding

Because women are born with a finite number of eggs, they are capable of passing on only about 14 de novo mutations to their offspring throughout their lifetime. In contrast, men are capable of forming de novo mutations each time they generate sperm, said Dr. Stefánsson.

Findings from the sequencing project indicate that on average, men form an additional 2 de novo mutations with each additional year of age at the time of conception of the child and that every 16.5 years, there is a doubling of de novo mutations in their sperm, which is quite "striking."

Previous investigations of de novo mutations through direct examination of parent-offspring transmission were largely limited to studying specific genes or regions.

To better understand the nature of these mutations, investigators sequenced 78 trios — a total of 219 distinct individuals — to identify single nucleotide polymorphism de novo mutations. Forty-four of the offspring had ASD, and 21 were schizophrenic. The other 13 offspring were included for a variety of reasons.

Relationships between parents' age and the number of mutations were examined using all 78 trios.

"The number of mutations increases with father's age...with an estimated effect of 2.01 mutations per year," they write. Maternal age was also associated with de novo mutations.

However, when both the father's and the mother's ages were entered into multiple regression analysis, the father's age remained highly significant (P = 3.3 x 10-8) whereas the mother's age did not (P = .49).

Furthermore, the researchers note that the study results "support the notion that the increase in mutations with parental age manifests itself mostly, maybe entirely, on the paternally inherited chromosome."

Explanation for ASD Increase?

In addition, the investigators point out that the observed effect of the father's age on ASD risk is limited to nonfamilial cases, defined as those cases in which the closest ASD relative is farther than cousins.

On the other hand, there is substantial variation in paternal de novo mutations, and in 1 of the models used by investigators, "97.1% of all these variations could be explained by the father's age and nothing else," Dr. Stefánsson said.

The finding that paternal age at conception is the dominant factor in determining the number of de novo mutations in the offspring suggests that paternal and not maternal age should be the real focus of concern when it comes to the possibility of passing on genetic mutations to children.

Indeed, note the investigators, Icelanders have recently transitioned from a rural to an urban 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.

This was followed by an "equally swift climb" back to 33 years in 2011 — primarily owing to the effect that higher education and the increased use of contraception had on reproduction.

Results from modelling studies developed by investigators showed that those born in 1900 carried, on average, 73.7 de novo mutations, whereas those born in 1980 carried, on average, only 59.7 such mutations — a decrease of 19.1%.

In contrast, the mutational load of individuals born in 2011 has increased by 17.2% to 69.9.

"Given that there is a rise in the mean age of fathers at conception in both Iceland and elsewhere, it is not unreasonable to propose that a significant part in the increase in reported ASD is due to the increasing age of fathers, so this paper shifts the age of the mother to the age of the father when it comes to concerns about developmental disorders," Dr. Stefánsson said.

A Contributing Factor

Mark Daly, PhD, Massachusetts General Hospital, Boston, told Medscape Medical News that the identification of increasing paternal age and increased risk of de novo mutations being passed on to the offspring is "quite conclusive and consistent" with hypotheses that date back to many of the early geneticists.

"What is most exciting about the study," he said, "is to now have the ability to do this kind of genome sequencing and to see it provide conclusive evidence that validate hypotheses that have been in the field a long time."

It is possible, he added, that the increasing age of fathers at conception might explain in part the apparent increase in the diagnosis of ASD in recent years.

On the other hand, "historically, the age of the father at conception has been much higher than it is today, so it's probably a contributing factor, but it'll take a lot of work before we can figure out how much of a contributing factor it is," Dr. Daly observed.

The study was a joint collaboration between deCODE Genetics, Reykjavik, Iceland, and Illumina Cambridge Ltd, Chesterford Research Park, and Little Chesterford, United Kingdom. Dr. Stefánsson is CEO of deCODE Genetics, but the study has no commercial application. Dr. Daly has disclosed no relevant financial relationships.

Nature. 2012;488:471-474. Abstract

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