Advancing grandparental age and autism risk

The paper by Emma Frans and colleagues* looking at autism risk across the generations is the focus of this post. Published in the journal JAMA Psychiatry alongside a provocative article by Andrea Roberts and colleagues** on maternal exposure to child abuse being "associated" with elevated risk for offspring autism (see here and here), the theme is transgenerational effects and quote: "that your father's and grandfather's lifestyle choices can affect you" as per some of media on this paper.

Ο Κακός Εγγονός @ Wikipedia  

I'm not going to head too heavily into the Frans study because others have already discussed it far better than I ever could (see here and here). Indeed NHS Choices carries a particularly good run-down of the study which is well worth a read (see here).

The main details were that based on an analysis of nearly 6000 cases of autism spectrum disorder (ASD) in Sweden, grandfathers who had fathered their daughter when aged 50 or above were 1.79 times more likely to have a grandchild diagnosed with autism than younger fathering grandfathers.

If grandfathers fathered a son when aged 50 or above, they were 1.67 times more likely to have a grandchild diagnosed with autism (again compared to grandfathers having children when they were younger).

The magic word 'epigenetics' is also mentioned to potentially account for results alongside the mutation side of things. I should also point out that Frans has published on similar things before with schizophrenia in mind***.

I'm interested in studies like the current Frans one despite their reliance on association and relatively limited increased risk of autism. Interested because alongside the 'older dads and autism risk' research (see here), I have actually talked about grandparents and risk of autism and schizophrenia previously on this blog (see here) based partly on some interesting data derived from ALSPAC published by Jean Golding and colleagues**** (open-access) and also that 2011 Frans study. In particular was the emphasis on the Golding 3M - meiotic mismatch methylation - hypothesis used to account for their results on grandmother's age as potentially being relevant to grandchild autism risk (please read the Golding article for more information on 3M complete with nice diagram).

I know it might sound a little far-fetched that the lives of our grandparents might so profoundly be able to affect the lives of subsequent generations but before we put this down to mere coincidence, let me draw your attention to some work that was done on a dark period of quite recent history: the Hongerwinter. The basics: the Dutch famine of 1944, where a Nazi blockade led to the deaths of thousands. As per the often cruel twists of fate, science actually learned something from the suffering of the Dutch people in these dark days. Not only the confirmation that wheat was tied into coeliac (celiac) disease but also the suggestion that famine exposure during a critical period of gestation *might* potentially affect offspring physical and mental health. I've kinda talked about something similar before with 'thin-fat bodies' and David Barker in mind (see here).

Granted in the current Frans study we are heading back even further through the germline as potentially hosting some effect, but to all intents and purposes, the theory is the same as per the intergenerational effects noted in other conditions like depression*****. I suppose one could ask whether specific types of autism might be more related to this grandparental age hypothesis over others. So for example, older grandparents at time of fathering or mothering impacting on the genome of their offspring - themselves then expressing certain traits associated with autism or the broader phenotype (not necessarily hitting the diagnostic threshold) - which are then transmitted (amplified?) to the next generation. Perhaps even some link to things like assortative mating theory too? I'm not saying that this is the only scenario and such 'transmission' works on its own to elevate risk of an autism diagnosis but the theory is an interesting one; even more so if we assume for example, that the autism and schizophrenia spectrums might not necessarily be poles apart (see here).

By the same token one might also extend such a hypothesis to include other variables other than just parental age at offspring conception. The availability of and exposure to certain food in these 'olden days', exposure events to pollutants, pharmaceuticals (yes, we did have them then) or lifestyle factors such as smoking and drinking habits, various psychological and somatic stressors; the list is seemingly endless. In at least some of these factors, there are subtle clues to potential future directions for autism research and beyond already being examined (see here and here). Assuming also that epigenetics might be tied into all of this, we also open up the concept of epigenetic reprogramming of the germline as per the very interesting article by Petra Hajkova****** (open-access); something which I think might be/have been discussed at the recent Environmental Epigenetics symposium hosted by the MIND Institute.

But let's not get too carried away with this area of inquiry or where it potentially leads in terms of the autism 'blame game'. Although I've not been able to find specific figures, I assume the actual numbers of grandfathers who fathered their children aged 50+ years is probably not going to be all that frequent if more current rates, at least here in the UK, are anything to go by (see this paper by Bray and colleagues*******). And then we have to wonder whether other variables might come into play such as the effect of paternal age at conception on birth factors such as birth weight or time of gestation even fecundity itself and how that might relate to autism risk.

Such transgenerational effects whilst interesting, should also not detract research attention away from other more here-and-now possibilities which might affect autism risk as per the recent valproate work or indeed all that immune activation research currently on-going. Neither should it deflect attention from the fact that the autism numbers are really starting to get quite serious - 1 in 50 US kids (with caveats) - and what needs to be done (a) asking why there is such an increase in cases and (b) to ensure the relevant help and support is available to all who need it.

To finish a very catchy tune from Jake Bugg - Lightning Bolt.

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* Frans EM. et al. Autism risk across generations. A population-based study of advancing grandpaternal and paternal age. JAMA Psychiatry. March 2013.

** Roberts AL. et al. Association of maternal exposure to childhood abuse With elevated risk for autism in offspring. JAMA Psychiatry. March 2013.

*** Frans EM. et al. Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective. Schizophr Res. 2011; 133: 120-124.

**** Golding J. et al. Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study. PLoS ONE. 2010; 5: e9939.

***** Warner V. et al. Grandparents, parents, and grandchildren at high risk for depression: a three-generation study. J Am Acad Child Adolesc Psychiatry. 1999; 38: 289-296.

****** Hajkova P. Epigenetic reprogramming in the germline: towards the ground state of the epigenome. Phil. Trans. R. Soc. B. 2011; 366: 2266-2273.

******* Bray I. et al. Advanced paternal age: How old is too old? J Epidemiol Community Health. 2006; 60: 851–853.

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Frans, E. (2013). Autism Risk Across GenerationsA Population-Based Study of Advancing Grandpaternal and Paternal AgeAutism Risk JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2013.1180