Tuesday, September 05, 2006

Paternal Age and Autism Risk

The Washington Post describes a new study by Abraham Reichenberg and colleagues showing a significant effect of paternal age on autism rates (link). The author, Shankar Vedantam, ends with this:
While the link between older fathers and autistic children is likely to be genetic, the researchers who conducted the new study also acknowledged the possibility that unknown other factors could simultaneously be causing men to delay parenthood while independently increasing autism rates.
It seems to me that, paradoxically, this is backwards. If paternal age itself somehow leads to autism, then the cause is less likely to be genetic (a father's genes don't change as he ages, but epigenetic factors could play a role). On the other hand, if there are factors that simultaneously delay parenthood and induce autism, those factors could be genetic. Under this hypothesis, fathers with certain alleles are more likely to be fathers late in life, and those same alleles, inherited by the child, could cause a predisposition towards autism.

4 comments:

s.h. said...

Have you heard of spontaneous mutations? Have you heard of James F. Crow? He says that the greatest mutational health hazard in the human population is the fertile old male. Read his article The High Spontaneous Mutation Rate: Is it a Health Risk PNAS 1994

Steve said...

I'm certainly familiar with both spontaneous mutations and James F. Crow. It seems unlikely that random genetic mutations would specifically cause autism, although I suppose that is possible.

Doug Scofield said...

The snideness of the remarks of "s.h." is quite uncalled for, but Crow's 1997 PNAS article points out several genetic diseases with risks that increase with paternal age; so this observation is (admittedly indirect) evidence for a genetic basis for autism... wouldn't an epigenetic basis be more suggested by a correlation with maternal age after correcting for paternal age?

Steve said...

I never meant to dispute the idea that mutations accumulate with paternal age. However, the cases that Crow points to in the 1997 PNAS article appear to involve a few genes that are somehow quite special. In a 2003 comment in Science, Crow describes them as "hot-spots occurring almost exclusively in males and rising steeply with age. Three genes--fibroblast growth factor receptor 3 (FGFR3, mutated in achondroplasia), FGFR2 (mutated in Apert's syndrome), and RET (mutated in multiple endocrine neoplasia)--are examples of the hot-spot class. In this class, genes carry mutations that are clustered at just one or two nucleotide sites." He then discusses at length the hypothesis that these specific mutations are selected in the male germ line, a hypothesis that Goriely et al. put right in the title of their article: "Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line." The title of Crow's commentary was "There's Something Curious About Paternal-Age Effects."

So, I'll concede the point that another such hotspot might be operating in autism, but whatever is going on with these hotspots is curious indeed, and I was looking for more ordinary explanations.