The association between old fathers and autism has been known for many years, and the most popular explanation has been genetic: sperm from older men are more likely to have accumulated DNA damage, which might lead to autism.As I've said before, this might explain some other puzzling things such as the fact that autism is more common in the wealthy; it might even explain any recent increases in the prevalence of autism, if people nowadays are waiting longer to have kids.
But there are other possibilities. It might be that the fathers of autistic people tend to have mild autistic symptoms themselves (which they do), and this makes them likely to delay having children, because they're socially anxious and so take longer to get married, or whatever. It's not implausible.
The new study aimed to control for this, by looking at parents who had two or more children, at least one of them with autism, and at least one without it. Even within such families, the autistic children tended to have older fathers when they were born - that is to say, they were born later. See the graphs below for details. This seems to rule out explanations based on the characteristics of the parents.
However, there's another objection, the "experienced parent" theory. Maybe if parents have already had one neurotypical child, they're better at spotting the symptoms of autism in subsequent children, by comparison with the first one.The authors tried to account for this as well, by controlling for the birth-order ("parity") of the kids. They also controlled for the mother's age amongst several other factors such as year of birth and history of mental illness in the parents. The results were still highly significant: older fathers meant a higher risk of autism. As if that wasn't enough, they also did a meta-analysis of all the previous studies and confirmed the same thing.
So overall, this is a very strong study, but there's a catch. The study population included over a million children (1,075,588) born in Sweden between 1983 and 1992. Of these, there was a total of 883 diagnosed cases of autism. That's a rate of 0.08%. In other words, although older fathers raised the risk of autism by quite a lot relatively speaking, the absolute rate was still tiny.
The most recent estimates of autism prevalence in Britain have put the figure at somewhere in the region of between 1% and 2% e.g. Baird et al (2006) and Baron-Cohen et al (2009) with American studies, using slightly different methods, generally coming in just below 1%. So the Swedish figure is more than 10 times lower than modern estimates. Whether this reflects different criteria for diagnosis, national differences, or increased prevalence over time, is debatable but it does raise the question of whether these findings still apply today.
The only way to know for sure would be to do a randomized controlled trial - get half your volunteer men to wait 10 years before having children - but I don't think that's going to happen any time soon...
Hultman CM, Sandin S, Levine SZ, Lichtenstein P, & Reichenberg A (2010). Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Molecular psychiatry PMID: 21116277
9 comments:
"The only way to know for sure would be to do a randomized controlled trial - get half your volunteer men to wait 10 years before having children - but I don't think that's going to happen any time soon..."
The way to do it would be through a sperm bank. That way you really could have a double-blind study. Though, I imagine the consent forms for that would be pretty complex.
A sperm bank is a very good idea actually. Tricky but not impossible.
I get that as a social study. Smart dads tend to marry later perhaps. But damaged DNA I presume won't interact properly when fertilization happens. So fusion of damaged DNA under womb conditions seems odd to me. Unless what we are witnessing is 'evolution'.
Sperm bank? That seems unethical. The only variable here is age right? Can't they test rats? Do older male rats reproduce hand flapping babies? more sensitive? or traits noticeably different to babies years earlier.
I don't think you could exclude aging of sperm while frozen, especially when they are frozen for 10 years or so.
I think that 0.08% prevalence must refer to autism proper. Any (and especially recent) studies that are quoting 1-2% prevalence will be looking at Autism Spectrum disorders, ranging from Asperger's, PDD-NOS, etc.. "Original", Kanner, autism was and is *rare*.
Catherina, I'm assuming it was in reference to the sperm donor. Finding data or asking sperm donors who donated their sperm 10 years ago to donate again. That just seems unethical to me. The study may not be consistent either. Do mothers resorting to IVF represent a randomized sample?
My impression of the current model for autism is that there are multiple loci all over the genome that have mutations, singly or in combination.
Rather than pursue a tedious study of human populations, why not cheat and do a reductionist study comparing sperm of males of different ages, or the same male over a long enough period to see the buildup of mutations?
This would depend on the technical feasibility of looking for rare mutations in a large population of sperm. Sequencing one sperm at a time would be expensive, but perhaps there are ways of selecting for mutated loci.
With the information in hand on where and how fast the mutations build up, we could go back and check the result with the known locations of mutation in autism.
The fact that there is a whole cluster of conditions associated with advanced paternal age, rather than just autism, also supports the idea that advanced paternal age implies greater mutation rates implies a higher frequency of mutation related conditions. The individual findings reinforce a larger theoretical mechanism.
If there is significant subclinical or latent inherited autism from parents that do not involve new mutations at the current generation, I would suspect that those tend to involve inheritance from mothers, rather than fathers. The much lower levels of clinically diagnosed autism in girls than boys suggests that some sex related factor may be reducing expression of autism in girls. But, when those girls grow up to have boys, the sex related suppressive factor may be gone.
For example, I'd predict that autistic children of young fathers disproportionately have maternal side family histories of autism.
Andrew: Interesting point.
There's certainly a bit of research arguing that there are differences in the families of "sporadic" autism (caused, presumably, by de novo mutations) as opposed to "familial" autism (i.e. where more than one child has autism), caused, presumably, by inherited factors.
This would predict that old fathers would tend to produce sporadic cases, and wouldn't have a FH of autism.
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