August
22, 2012 - Older men are more likely than young ones to father a child who
develops autism or schizophrenia,
because of random mutations that become more numerous with advancing paternal
age, scientists reported on Wednesday, in the first study to quantify the effect
as it builds each year. The age of mothers had no bearing on the risk for these
disorders, the study found.
Experts said that the finding was hardly reason to
forgo fatherhood later in life, though it might have some influence on
reproductive decisions. The overall risk to a man in his 40s or older is in the
range of 2 percent, at most, and there are other contributing biological
factors that are entirely unknown.
But the study, published online in the
journal Nature, provides support for the argument that the surging rate of
autism diagnoses over recent decades is attributable in part to the increasing
average age of fathers, which could account for as many as 20 to 30 percent of
cases.
The findings also counter the longstanding assumption
that the age of the mother is the most important factor in determining the odds
of a child having developmental problems. The risk of chromosomal
abnormalities, like Down syndrome,
increases for older mothers, but when it comes to some complex developmental
and psychiatric problems, the lion’s share of the genetic risk originates in
the sperm, not the egg, the study found.
Previous studies had strongly suggested as much,
including an analysis published in April that found that
this risk was higher at age 35 than 25 and crept up with age. The new report
quantifies that risk for the first time, calculating how much it accumulates
each year.
The research team found that the average child born to
a 20-year-old father had 25 random mutations that could be traced to paternal
genetic material. The number increased steadily by two mutations a year,
reaching 65 mutations for offspring of 40-year-old men.
The average number of mutations coming from the
mother’s side was 15, no matter her age, the study found.
“This study provides some of the first solid scientific
evidence for a true increase in the condition” of autism, said Dr. Fred R.
Volkmar, director of the Child Study Center at the Yale School of Medicine, who
was not involved in the research. “It is extremely well done and the sample
meticulously characterized.”
The new investigation, led by the Icelandic firm Decode
Genetics, analyzed genetic material taken from blood samples of 78 parent-child
trios, focusing on families in which parents with no signs of a mental disorder
gave birth to a child who developed autism or schizophrenia. This approach
allows scientists to isolate brand-new mutations in the genes of the child that
were not present in the parents.
Most people have many of these so-called de novo
mutations, which occur spontaneously at or near conception, and most of them
are harmless. But studies suggest that there are several such changes that can
sharply increase the risk for autism and possibly schizophrenia — and the more
a child has, the more likely he or she is by chance to have one of these rare,
disabling ones.
Some difference between the paternal and maternal side
is to be expected. Sperm cells divide every 15 days or so, whereas egg cells
are relatively stable, and continual copying inevitably leads to errors, in DNA
as in life.
Still, when the researchers removed the effect of
paternal age, they found no difference in genetic risk between those who had a
diagnosis of autism or schizophrenia and a control group of Icelanders who did
not. “It is absolutely stunning that the father’s age accounted for all this
added risk, given the possibility of environmental factors and the diversity of
the population,” said Dr. Kari Stefansson, the chief executive of Decode and
the study’s senior author. “And it’s stunning that so little is contributed by
the age of the mother.”
Dr. Stefansson’s co-authors included C. Augustine Kong
of Decode, and researchers from the University of Iceland, Aarhus University in
Denmark and Illumina Cambridge Ltd.
Dr. Stefansson said it made sense that de novo mutations
would play a significant role in brain disorders. At least 50 percent of active
genes play a role in neural development, so that random glitches are more
likely to affect the brain than other organs, which have less exposure.
In the end, these kinds of mutations may account for 20
to 30 percent of cases of autism, and perhaps schizophrenia, some experts said.
The remainder is probably a result of inherited genetic predisposition and
environmental factors that are the subjects of numerous studies.
Dr. Stefansson and other experts said that an increase
in the average age of fathers had most likely led to more cases of autism.
Unlike other theories proposed to explain the increase, like vaccinations,
it is backed by evidence that scientists agree is solid.
This by itself hardly explains the overall increase in
diagnoses, at least in the United States. The birthrate of fathers age 40 and
older has increased by more than 30 percent since 1980, according to government
figures, but the diagnosis rate has jumped tenfold, to 1 in 88 8-year-olds.
And it is not clear whether the rate of schizophrenia
diagnosis has increased at all in that time.
Nonetheless, if these study findings hold up and extend
to other brain disorders, wrote Alexey S. Kondrashov of the University of
Michigan, in an editorial accompanying the study, “then
collecting the sperm of young adult men and cold-storing it for later use could
be a wise individual decision.”
That very much depends on the individual. “You are going to have guys who look at this and say, ‘Oh no, you mean I have to have all my kids when I’m 20 and stupid?’ ” said Evan E. Eichler, a professor of genome sciences at the University of Washington in Seattle. “Well, of course not. You have to understand that the vast majority of these mutations have no consequences, and that there are tons of guys in their 50s who have healthy children.”