How helpful is a 'geek index'?

A quote to begin: "male offspring of older fathers had higher ‘geek index’ scores, a composite measure of high IQ, strong focus on the subject of interest and social aloofness."

So said the findings published by Magdelena Janecka and colleagues [1] (open-access) who set out to determine whether "having an older father is associated with certain beneficial traits" in offspring. Their use of the term 'geek index' (GI) was derived from a "composite measure of non-verbal intelligence, restrictive interests and reduced need to fit in with the peer group" based on data derived from the TEDS (Twin Early Development Study) initiative (something that has cropped up before on this blog). As one might imagine, use of the term 'geek index' in a science article was always likely to make some media headlines (see here for example).

In terms of study design and numbers, this was a biggie with study participants in the thousands. The geek index was derived from scores "of (i) non-verbal intelligence, (ii) restrictive and repetitive behaviours (RRBs) and (iii) social aloofness." Further: "Scores on the Raven’s Standard Progressive Matrices test were used to obtain (i). Childhood Autism Spectrum Test (CAST) scores were used to obtain both (ii) and (iii)." Various statistical 'transformations' were conducted on said scores to give that geek index sum and, not forgetting the parental age bit, paternal age was also thrown into the statistical mix.

As per the opening sentence, those children born to older fathers (but not older mothers) seemed to more frequently present with a higher geek index. This association persisted after controlling for various potentially confounding variables: "maternal age, sex, zygosity and SES [socio-economic status]." Researchers further observed that: "GI was positively linked with future academic attainment—including the key predictors of future SES—suggesting a phenotypic advantage in the offspring of older fathers."

These are interesting results and notwithstanding some study limitations i.e. "It was not possible to determine whether the advantageous effects of GI extend beyond secondary education, and correlate with future SES" require further independent investigation. Offspring being born to older fathers has generally been associated with various less-than-positive outcomes so this article kinda paints a more positive picture for children and families. Indeed, one of the commentators talking about these findings suggests that "perhaps we are destined for future society of geniuses that are going to help us solve all the world's problems." One would hope so.

As per the title of this post, I would however question how useful/helpful the term 'geek index' is when it comes to outcomes and implications. Yes, I know there is such a thing as 'geek chic' these days, but let's not forget that the word 'geek' has it's primary origins as a term of ridicule in many languages. To quote one definition: "the word typically connotes an expert or enthusiast or a person obsessed with a hobby or intellectual pursuit, with a general pejorative meaning of a "peculiar person, especially one who is perceived to be overly intellectual, unfashionable, or socially awkward."" I'm not so sure that every child (youngster or teenager) would be particularly happy to be labelled as scoring high on a geek index. Surely something a little more scientific could replace such a term?

Going also back to those study caveats provided by the authors, I might also raise the idea that just because someone shows an intellectual advantage when it comes to something like STEM (science, technology, engineering and mathematics) subjects does not necessarily mean that their future is going to be a rosy one in terms of employment, income or other markers of SES. “If you look at who does well in life right now, it’s geeks” is one of the quotes attributed to the first author of the paper; and with it as massive a sweeping generalisation as you will ever see.

If we for example, assume that strengths in STEM might be over-represented when it comes to the autism spectrum (see here) we should be seeing lots and lots of people either diagnosed with autism or possessing significant autistic traits thriving in such roles and in life in general. The reality however is that skills pertinent to STEM often do not appear in a vacuum (see here) as I would put forward the suggestion that future research might also consider the possibility of a relationship between the geek index (or other term) and the presentation of something like anxiety or depression and how that might also impact on later adult outcomes for example. The additional idea that social aloofness also makes up part of the geek index is something else that needs quite a lot more work on as part of any 'advantage' arguments being put forward...

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[1] Janecka M. et al. Advantageous developmental outcomes of advancing paternal age. Translational Psychiatry. 2017. 7; e1156.

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Is parental age difference important for offspring autism and schizophrenia risk?

In answer to the question that titles this post on whether parental age differences at offspring conception might matter when it comes to offspring risk of autism or schizophrenia, the answer is very possibly. As the paper by Byars & Boomsma [1] (open-access) reports: "Our study shows that autistic and schizophrenic disorder risks tend to be higher, in more dissimilarly aged parents, relative to parents with the most similar ages." This age disparity issue has been mentioned previously in the peer-reviewed science literature [2] (see here for my take).

The Byars / Boomsma paper does contain a lot more information than merely whether parents dissimilar ages might advance some risk for offspring such as adding more substance to the idea that: "Older fathers and mothers both conferred increased risk for autistic but not schizophrenic disorders" (see here for some previous discussions on this issue). They also talk about their data reflecting possible "epigenetic maternal mechanisms that control patri/matrigenic parent-of-origin effects on foetal growth or offspring brain development" alongside how age might confer more "mutational load" for sperm over eggs. For some further discussion about such issues, I would draw readers attention to an interesting post that appeared on the Spectrum website a few moons ago (see here).

A few important details to point out about the Byars / Boomsma paper: "The final sample included 1 646 092 offspring that were never diagnosed with a mental disorder during the study period while 94 177 (5.41%) were diagnosed within one of the autistic or schizophrenic disorder groups." With those kind of figures it's not surprising that this is yet another study reliant on those very useful Scandinavian registries (Denmark). As well as coding participants' parents in age brackets, researchers also included an impressive lists of co variates in their statistical modelling covering maternal 'pre-exisiting' conditions, pregnancy related variables and "education and average income". They also included a rather pretty diagram to [speculatively] convey their main message (see here).

The idea that parental age might somehow be implicated in risk of various psychiatric / behavioural labels to offspring has been around for some time. Combined with factors such as the inter-pregnancy interval (IPI), there is some quite strong population evidence emerging implicating such issues in relation to risk. I personally think this kind of work is important in light of what is being noted in population trends when it comes to starting a family for example. That being said, a lot more needs to be done on the potential mechanisms behind such trends including how sperm for example, pick up their 'deletions and duplications' over time [3] (thanks Robert for the link). Indeed, the word 'methylation' might also be important to this topic [4]...

With specific regards to the possible mechanisms behind the parental age disparity finding, I can honestly say that at the moment, I just don't have any reliable ideas as to why...

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[1] Byars SG. & Boomsma JJ. Opposite differential risks for autism and schizophrenia based on maternal age, paternal age, and parental age differences. EMPH. 2016: 286-298.

[2] Sandin S. et al. Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry. 2016 May;21(5):693-700.

[3] Molina O. et al. Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions and duplications: a FISH approach. Hum Genet. 2011 Jan;129(1):35-44.

[4] Atsem S. et al. Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation. Hum Mol Genet. 2016 Sep 23. pii: ddw328.

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Byars SG, & Boomsma JJ (2016). Opposite differential risks for autism and schizophrenia based on maternal age, paternal age, and parental age differences. Evolution, medicine, and public health, 2016 (1), 286-98 PMID: 27637201

Offspring autism risk and advancing parental age (differences)

Parental age at offspring conception/birth in relation to offspring autism risk has been a recurrent theme in autism research circles for quite a few years now. I've covered it more than once on this blog (see here for example) and the various suggestions that advancing parental age in particular, might elevate the risk of offspring autism.

Set in this context, the paper by Sven Sandin and colleagues [1] (open-access) (a name not unfamiliar to this blog) adds to the research evidence based on their analysis of some 5.7 million children born between 1985 - 2004 resident in one of five countries (Denmark, Israel, Norway, Sweden and Western Australia). Including data on some 30,000 children diagnosed with an autism spectrum disorder (ASD): "Parental ages, sex and birth year were obtained from birth or civil registers."

After quite a bit of statistical modelling and controlling for various potentially confounding variables, several findings were reported pertinent to the authors' data being "the strongest evidence to date supporting the hypothesis that advanced parental ages at the time of birth are independently associated with risk for ASD in the offspring." Outside of "no support for any modification by the sex of the child" researchers also noted a "combined parental age effect" whereby there "was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages."

A few of the finer details of this study have been covered elsewhere (see here). I'll draw your attention to one or two statistics unearthed during the study:

• "relative to fathers aged 20–29 years, fathers 50 years or older had a statistically significantly increased risk for offspring with ASD (RR=1.66 95% CI:1.49–1.85)",
• "Relative to mothers aged 20–29 years, mothers younger than 20 years had a statistically significantly increased risk for offspring with ASD (RR=1.18 95% CI:1.08–1.29)" and 
• the "lowest risk corresponded to couples that generated the majority of births, specifically, 29–39-year-old fathers and 25–35-year-old mothers." 

Those estimates of relative risk (RR) statistics translate into an estimated 66% increased risk for offspring autism if a dad was over 50 years old compared with a dad in their 20s, an 18% increased risk for offspring autism for teen mums compared to 20-something mums and the lowest statistical risk of offspring autism being reported when dads conceive in their 30s coupled with a mid-20 to mid-30 year old mum. The authors also note that "Similar patterns of association, but with slightly higher RRs for the highest parental ages, were evident for AD [autistic disorder]" so completing the message about older parental ages at conception and differing parental ages being relevant across the autism spectrum.

Accepting that this was a huge study in terms of participant numbers and spanning different geographical locations, the authors rightly offer a few words of caution about their methods and data. So: "we lack information about potentially confounding variables such as SES [socio-economic status] and parental psychiatric history" is something to keep in mind [2]. Further: "We cannot rule out the possibility that other factors associated with parental age (for example, length of marriage or partnership, obstetric complications, gestational age and birth weight) have an important role in explaining our results" and "We did not have individual level information on co-morbid ID [intellectual disability] in ASD cases." I'd also suggest that given the growing emphasis on autism or ASD not existing in some sort of diagnostic vacuum (see here) one might reasonably ask whether other comorbidity outside of ID might also play a role in risk estimates.

As to the possible mechanism(s) of effect, well, the authors go through the usual older parents - older sperm and eggs mantra although perhaps bypassing an emerging area outside of just de novo mutations based on the role of epigenetic mechanisms (see here). They do suggest that the 'difference in parental age' factor might suggest "that the increase in risk is not attributable to advancing parental age per se, and that the risk increase cannot be explained solely by an accumulation of point mutations or other genomic alterations in the parents" but say little more on the basis of their collected data.

I might be wrong but I also didn't seem too much in the way of discussion of how parental nutrition might impact on offspring autism risk as per the proposed factor from other work by authors on the Sandin paper in relation to the inter-pregnancy interval (IPI) and autism risk (see here and see here). Although the idea that parental age might affect autism offspring risk, I'd be minded to suggest that this is only the first stage in a journey towards elucidating the particular mechanisms of any effect.

Music: The Pixies - Gigantic.

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[1] Sandin S. et al. Autism risk associated with parental age and with increasing difference in age between the parents. Mol Psychiatry. 2015 Jun 9.

[2] Lehti V. et al. Maternal socio-economic status based on occupation and autism spectrum disorders: A national case-control study. Nord J Psychiatry. 2015 Mar 3:1-8.

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Sandin S, Schendel D, Magnusson P, Hultman C, Surén P, Susser E, Grønborg T, Gissler M, Gunnes N, Gross R, Henning M, Bresnahan M, Sourander A, Hornig M, Carter K, Francis R, Parner E, Leonard H, Rosanoff M, Stoltenberg C, & Reichenberg A (2015). Autism risk associated with parental age and with increasing difference in age between the parents. Molecular psychiatry PMID: 26055426

Autism research in Jamaica

For the past couple of years I've been tracking some rather interesting publications coming out of data from Jamaica on the topic of autism / autism spectrum disorder (ASD) specifically looking at the possible overlap between genes and various environmental factors. I thought now would be a good time to bring this collection of papers to the blogging table and summarise their findings based on the analysis of data collected from The Jamaican Autism study. The fact that their latest research foray mentions some of the genetics of glutathione [2] with autism in mind is very interesting in light of some other findings in this area (see here). There's more on this shortly.

You're not Absolem. I'm Absolem. Stupid girl.

So:

Study 1: Maternal and paternal age are jointly associated with childhood autism in Jamaica [2].
Higher parental age - both mother and father age - seemed to be associated with a diagnosis of autism/ASD in offspring. Higher maternal age in particular, survived further statistical analysis as being a potentially important factor. This is a topic which has cropped up in autism research circles before (see here).

Study 2: Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders [3].
"Our findings do not support an association between blood mercury concentrations measured in Jamaican children 2–8 years of age and ASD case status." Such a conclusion was based on the analysis of blood mercury concentrations between ASD cases and a control group, and took into account important factors such as seafood consumption bearing in mind what is known about such a foodstuff and environmental exposures (see here).

Study 3: The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders [4].
Blood arsenic levels were the focal point of this study, and a familiar conclusion to the previous study: "Our results do not support an association between postnatal total blood arsenic measured in Jamaican children 2-8 years of age and ASD case status." Again the consumption of certain foodstuffs seemed to be important correlates related to any elevated levels of arsenic detected.

Study 4: Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder [5].
Cadmium levels this time around, and again: "we did not find any significant differences between ASD cases and typically developing (TD) controls with respect to the 75th percentile of blood cadmium concentrations." Food (yes again) seemed to be a good correlate linked to differences in blood cadmium levels.

Study 5: Blood manganese concentrations in Jamaican children with and without autism spectrum disorders [6].
Manganese, and wait for it... "Our results do not indicate a relationship between postnatal BMC [blood manganese concentrations] and ASD case status of Jamaican children ages 2–8 years."

Study 6: Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder [7].
Lead (Pb), a favourite topic of this blog, was the metal of choice when it came to analysis to see if there was any connection between the stuff and autism. Er,... "Our results do not support an association between postnatal blood lead concentration measured in Jamaican children 2–8 years of age and ASD case status."

I think you can see the trend coming out of this data examining samples of children living in Jamaica with and without autism. Perhaps just as important are the various discussions about the ways and means that participants might have been exposed to these various metals and how one needs to be aware of how food in particular, could be a significant source of exposure. This perhaps puts a new slant on previous studies which have suggested an increased body burden of certain metals to be associated with autism (see here) and the question of whether dietary sources of such metals have adequately been taken into account. Don't get me wrong, I'm still very keen to see more 'metallomics' applied to autism research (see here), perhaps just controlling for a few more potentially important confounders.

The Jamaican Autism study also provides quite a nice template for setting up further geographically distinct initiatives to compare and contrast with/against. I note for example that the recent study from Hodgson and colleagues [8] looking at autism in Oman (itself the topic of quite a few peer-reviewed publications) suggested some rather different results for their cohort: "Mercury levels were markedly elevated in the hair of autistic subjects vs. control subjects" albeit based on hair analysis not blood. With the previous caveat about confounders in operation, one wonders whether there may be more to see across different countries particular when bringing into play the potential importance of that glutathione connection which has also previously received some mention in the Jamaican autism studies [9].

And then some music. Jamaica and music, mmm... One Love.

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[1] Rahbar MH. et al. nteraction between GSTT1 and GSTP1 allele variants as a risk modulating-factor for autism spectrum disorders. Research in Autism Spectrum Disorders. 2015; 12: 1-9.

[2] Rahbar MH. et al. Maternal and paternal age are jointly associated with childhood autism in Jamaica. J Autism Dev Disord. 2012 Sep;42(9):1928-38.

[3] Rahbar MH. et al. Seafood consumption and blood mercury concentrations in Jamaican children with and without autism spectrum disorders. Neurotox Res. 2013 Jan;23(1):22-38.

[4] Rahbar MH. et al. The role of drinking water sources, consumption of vegetables and seafood in relation to blood arsenic concentrations of Jamaican children with and without Autism Spectrum Disorders. Sci Total Environ. 2012 Sep 1;433:362-70.

[5] Rahbar MH. et al. Role of fruits, grains, and seafood consumption in blood cadmium concentrations of Jamaican children with and without Autism Spectrum Disorder. Res Autism Spectr Disord. 2014 Sep 1;8(9):1134-1145.

[6] Rahbar MH. et al. Blood manganese concentrations in Jamaican children with and without autism spectrum disorders. Environ Health. 2014 Aug 23;13:69.

[7] Rahbar MH. et al. Blood Lead Concentrations in Jamaican Children with and without Autism Spectrum Disorder. Int J Environ Res Public Health. 2014 Dec 23;12(1):83-105.

[8] Hodgson NW. et al. Decreased glutathione and elevated hair mercury levels are associated with nutritional deficiency-based autism in Oman. Exp Biol Med (Maywood). 2014 Jun;239(6):697-706.

[9] Rahbar MH. et al. Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder. Int J Environ Res Public Health. 2014 Aug 6;11(8):7874-95.

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Rahbar MH, Samms-Vaughan M, Loveland KA, Pearson DA, Bressler J, Chen Z, Ardjomand-Hessabi M, Shakespeare-Pellington S, Grove ML, Beecher C, Bloom K, & Boerwinkle E (2012). Maternal and paternal age are jointly associated with childhood autism in Jamaica. Journal of autism and developmental disorders, 42 (9), 1928-38 PMID: 22230961

Increasing parental age and autism severity?

An interesting paper by David Geier and colleagues [1] (open-access here) caught my eye recently, concluding that there was a lack of support for the suggestion that: "increasing parental age was associated with increasing autism spectrum disorder phenotypic severity".

"the snozzberries taste like snozzberries".

Before progressing through the paper and its possible implications, the eagle-eyed out there might have already spotted the name Dr Brian Hooker on the authorship list of the Geier paper. Outside of his other peer-reviewed work [2], I probably only need to mention the letters 'CDC' and everything that has [so far] followed including (at the time of writing) a removal statement retraction statement (updated: 04/10/14) for another paper [3]...

Anyhow, the idea behind the Geier paper stems from the quite widely disseminated notion that there may be a connection between increasing parental age at conceiving and an increased risk of offspring autism. I've covered it a few times on this blog (see here and see here). The authors elaborate about a recent hypothesis suggesting that "there must be a linkage between increasing genetic load and increasing parental age in autism spectrum disorder pathogenesis" based on studies like the one from Kong and colleagues [4] (covered in a previous post) and Lampi and colleagues [5]. Further, that as a consequence of an increasing genetic load (all those SNPs et al), "there should be a significant relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity of subjects diagnosed with an autism spectrum disorder".

The paper is open-access but maybe a few details are in order:

• Participants (N=351), diagnosed with DSM-IV autism, were drawn from "patients presenting for outpatient genetic consultations at the ASD Centers, LLC". Mean age was approximately 9 years of age, most male and most reporting developmental regression following birth. Details of age of parents at time of offspring birth were analysed alongside use of the ATEC (Autism Treatment Evaluation Checklist) at initial clinical presentation. These variables formed the crux of the study.
• Results: "Overall, it was observed that no significant relationships were observed between increasing autism spectrum disorder phenotypic severity and increasing maternal or paternal age". Except, that is, for something that seemed to suggest that older maternal age at birth of child seemed to correlates with "improved sociability" in offspring. The authors report that their observations: "provide important insights into the apparent lack of a relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity".

Of course one has to be careful with any study of correlation/association, particularly when it comes to something as simple as just looking at ATEC scores of severity of behaviours in the autism domains and parents age at time of birth of their children. I personally would also have liked to see some further discussion on whether the broader autism phenotype (BAP) for example, might have been an influencing variable too in light of studies like the one from Hasegawa and colleagues [6]. Also, the participant group is quite large - as the authors note - but even there I think back to the sort of sample numbers that those [big data] studies in Taiwan are including (see here) as to where we should be heading.

That all being said, I don't want to downplay the Geier results. Another quote might be useful here: "most observed de novo genetic events are unconnected to an autism spectrum disorder diagnosis, and those that do confer risk are distributed across many genes and are not necessarily sufficient for disease". This ties in rather nicely with the recent discussions on common variations and autism risk (see here) and how Gaugler and colleagues [7] questioned how much weight to give to de novo mutations in the grand scheme of autism 'causation'. This also might imply that non-genetic events, or at least non-structural genetic events headed under the general banner of environment might also play some contributory role to at least some cases of autism. Again, something which has cropped up on this blog before (see here).

Music to close. Given the recent vote near these parts, one of Scotland's most famous exports... Franz Ferdinand and Do You Want To.

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[1] Geier DA. et al. An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. J Child Neurol. 2014 Aug 27. pii: 0883073814541478.

[2] Hooker B. et al. Methodological issues and evidence of malfeasance in research purporting to show thimerosal in vaccines is safe. Biomed Res Int. 2014;2014:247218.

[3] Hooker BS. Measles-mumps-rubella vaccination timing and autism among young african american boys: a reanalysis of CDC data. Transl Neurodegener. 2014; 3: 16.

[4] Kong A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5.

[5] Lampi KM. et al. Parental age and risk of autism spectrum disorders in a Finnish national birth cohort. J Autism Dev Disord. 2013 Nov;43(11):2526-35.

[6] Hasegawa C. et al. Broader autism phenotype in mothers predicts social responsiveness in young children with autism spectrum disorders. Psychiatry Clin Neurosci. 2014 Jun 6. doi: 10.1111/pcn.12210.

[7] Gaugler T. et al. Most genetic risk for autism resides with common variation. Nature Genetics. 2014. July 20.

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Geier DA, Hooker BS, Kern JK, Sykes LK, & Geier MR (2014). An Evaluation of the Effect of Increasing Parental Age on the Phenotypic Severity of Autism Spectrum Disorder. Journal of child neurology PMID: 25163730

De novo mutations, older dads and autism (again)

Those with an interest in autism (and/or schizophrenia) will have probably already seen the headlines discussing the study by Augustine Kong and colleagues* on  the rate of de novo genetic mutations and a father's age as being potentially important for conditions like autism and schizophrenia. For those like me who are still struggling with all things mutation, quite a nice summary of the current research is offered in this Nature commentary accompanying the study.

I'm going to briefly focus on the potential implications specifically for autism in this post, accepting that (a) de novo mutations have been looked at with schizophrenia in mind (see here) and (b) increasing parental (and grand-parental) age has been linked to an increased risk of schizophrenia (see here).

This is not the first time this year that findings related to de novo mutation and paternal age in relation to autism have surfaced in Nature as discussed in this post. The latest study from Kong and colleagues suggests a few things:

• The entire genome of 78 families (mum, dad, child) of Icelandic-origin was sequenced.
• They studied the small genetics changes, SNPs, in and between mums and dads and their children, taking into account the age of the parents. Apparently of the offspring included for study, 44 had received a diagnosis of an autism spectrum disorder and 21 diagnosed with schizophrenia.
• Their analysis suggested (i) fathers passed on about four times more mutations than mothers, (ii) approximately 2 new mutations were present in children for every year of increase in the father's age at conception - so a father conceiving at 20-years old passed on 25 random mutations compared with a father conceiving at 40-years old who passed on 65 mutations, (iii) mums were reported to pass on about 15 mutations irrespective of age; thought due to the fact that women carry their eggs through life whilst sperm is constantly being produced and therefore potentially subject to the rigours of ageing and environment.

There has, understandably, been some discussion about the implications of this research with regards to autism and more generally about the trend towards couples starting families when they're getting on a bit. Kari Stefansson, lead author on the paper discusses the trend (in Iceland) towards increasing paternal age when conceiving a child - 27.9 years in 1980 to 33 years in 2011 - as a case in point and potentially what implications this may have. That being said, I have to say that I raised a smile when reading about this recent research which suggested that children with older fathers might actually be genetically-programmed to live longer as a function of increasing teleomere length with age in sperm**. I am comparing apples and oranges here but want to show how such things are never straight-forward.

Another debate has also seemingly arisen from the Kong study with regards to the numbers of children with autism being currently diagnosed/estimated, and whether the figures reflect better case ascertainment, etc. or are reflective of a true increase in the numbers of people with autism. To quote from Fred Volkmar (here) "This study provides some of the first solid scientific evidence for a true increase in the condition of autism". Earlier this year I discussed the latest estimates of autism in the United States produced by the CDC and how an estimated 1 in 110 8-year olds with autism became 1 in 88 8-year olds with autism. If accurate, what Dr Volkmar seems to be suggesting is a kind of bridge between the genetics-environment camps which will almost certainly impact on the autism numbers game: older parents, older fathers passing on a greater number of mutations potentially increasing the risk of autism or schizophrenia. I pass no judgement on this proposal by the way.

There are a few final comments to make on this research and the area in general. Regular readers of this blog might already know that I am becoming a bit of a fan of the area of epigentics and the promise that it might hold for conditions like autism. Noting the recent research from Richard Anney and colleagues ("no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level") it's all well and good suggesting that older fathers might increase the risk of autism, but without such details as to which SNPs are consistently and reliably at work, there is likely to be a whole lot more involved in the aetiology of autism than just the structure of the genome. That and my continuing questioning as to whether age is the only factor in causing mutation or whether other environmental 'exposures' might also exert an effect.

Additionally and finally, I've said it before and I'll say it again: autism is not a homogeneous condition. We might talk about autism as being diagnostically homogeneous insofar as a person presents with this triad (soon to be dyad) of symptoms and the autism diagnosis box is ticked, but symptom onset and presentation varies from person to person (endophenotype to endophenotype?) and is further complicated by elevated risk for various comorbidity, psychological, cognitive and also more somatic comorbidity. I see nothing in the current research that rules out the possibility that more mutations passed to offspring as a result of older dads might not also be tied into an increased risk for other things (autoimmune features and conditions, epilepsy, learning disability, depression, anxiety, etc., etc.). Until we can, with some degree of confidence, peel back the diagnostic and risk layers, this issue will be in the background of any autism research.

Don't get me wrong, I am very interesting in the latest results from Kong and the now replicated findings of advancing paternal age and risk in some cases of autism. I do however believe that within the context of all the other research published and on-going in autism, this might be but one small piece of a much larger puzzle on aetiology and underlying pathology.

To finish, Jim Morrison has been on my musical radar of late, so how about some Riders on the Storm?

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* Kong A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012; 488: 471-475.

** Eisenberg DTA. et al. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. PNAS. 2012; 109: 10251-10256.

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Augustine Kong, Michael L. Frigge, Gisli Masson, Soren Besenbacher, Patrick Sulem, Gisli Magnusson, Sigurjon A. Gudjonsson, Asgeir Sigurdsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Wendy S. W. Wong, Gunnar Sigurdsson, G. Bragi Walters, Stacy Steinberg, Hannes Helgason, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Agnar Helgason, Olafur Th. Magnusson,, Unnur Thorsteinsdottir, & Kari Stefansson (2012). Rate of de novo mutations and the importance of father’s age to disease risk Nature DOI: 10.1038/nature11396

Rich kids, older dads and autism? Or poor kids, older mums and autism?

I'm confused.

I must admit that it is fairly easy to confuse me as family members and work colleagues will readily attest. Not to dwell too much on the point but I'm the sort of chap who easily gets lost even with a map and car GPS, to the cries of "we've been past that building already" and "just ask someone". Given that I am a man, asking someone for directions is just not in my vocabulary.

The source of my current confusion is contained in one edition of the Journal of the American Academy of Child & Adolescent Psychiatry (JAACAP) containing two papers published fairly recently. The first by Rai and colleagues* reports on parental socio-economic status (SES) and risk of offspring autism in Sweden. The second is by Sandin and colleagues** looking at advancing maternal age and risk of offspring autism. The results: kids with a lower SES in Sweden have a greater risk of autism and older mums conceiving later might increase the risk of their children being diagnosed with autism.

A short summary of the Rai paper first:

• Rai et al were intrigued about how the data on SES and autism (high family SES = increased risk of offspring autism) seemed to fly in the face of many other conditions where lower SES increased risk. 
• Based on a total population of just over half a million children aged 0-17 years living in Stockholm county between 2001-2007, they wanted to look at the 5000 or so cases of autism included in the population, matched 10-1 with age and gender controlled asymptomatic children, to see if SES factors were relevant. 
• Importantly, they controlled for various potential sources of bias including things like parental age, migration status and various birth characteristics.
• Results: lower SES seemed to be associated with a risk of autism in offspring.

And for the Sandin paper:

• A slightly different approach based on a meta-analysis of epidemiological studies reporting on autism up to January 2012.
• Sixteen publications met their criteria for study inclusion resulting in a total sample population of just over 25,000 people with autism - autism spectrum conditions - compared with 8.5 million controls.
• Results: based on various analyses of age and age-brackets, a dose response effect of maternal age on risk of offspring autism was apparent in most studies. So older mums with a greater 'age dose' were at greater risk of having a child with autism. Mums who were 35 years old or older at conception/birth were about 1.5 times more likely to have a child with autism compared to those mums falling into the 25-29 years age bracket. Interestingly, young mums (below 20 years of age) showed a significant decrease in risk of offspring autism.

Why then my confusion?

Well as has been pointed out by a few people in the Twitter-sphere, quite a lot of data has already been produced and published suggesting that SES might have a link to autism risk; the findings generally reporting that kids from families with a higher SES (rich kids) might be at greater risk than their poorer counterparts. Added to the fact that quite a lot of attention has also been directed to older dads, older sperm and more possibility of some kind of genetic-environmental effect being linked to an increased risk of autism in offspring - remembering the Nature papers on de novo mutation and dads recently - you can perhaps see why I might be a little confused with these results which seem to suggest something slightly different.

I hasten to add that I am not questioning the studies, current or previous, how they were carried out or anything like that, it's just that with all the fuss being made about factors like higher SES and paternal age, one can't help but wonder if such issues are as definitive as they are often portrayed. Of course there are caveats to such generalisations. Who was looked at and where do they live alongside the myriad of interfering variables which might not be controlled for. Autism being an extremely heterogeneous condition with aetiology most likely linked to lots and lots of different factors variably depending on genes and environment should also not be forgotten. I hark back to other studies on SES and autism which to some degree substantiate the current findings from Rai and colleagues; to quote from King & Bearman*** (full-text) "We find that the socioeconomic gradient for autism has begun to reverse".

Still, what these latest figures serve to show is that autism is still very much of an enigma and one should always be wary of sweeping generalisations when it comes to risk. The added assumption also when asking questions like "what causes autism" or rather "what factors are associated with the increase in cases of autism", as well as being mindful of heterogeneity and comorbidity, we should also be responsive to the fact that the causes may be fluidic and fluctuating. What might drive increase in one cohort at one time period, may not necessarily carry the same weight in others at other times. I will talk more about this in subsequent posts on the back of some interesting suggestions regarding environmental pollutants (see here for a sneak preview of the research).

To finish, I'm minded to suggest something a little bit lively to relieve me of my confusion. How about a spot of B52s?

* Rai D. et al. Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study. JAACAP. 2012; 51: 467-476.

** Sandin S. et al. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. JAACAP. 2012; 51: 477-486

*** King MD. & Bearman PS. Socioeconomic status and the increased prevalence of autism in California. American Sociological Review. 2011; 76: 320-346.

Dust settled: autism, de novo mutations and older dads

On purpose I have left it a few days to post about the trio of studies published in Nature by Sanders and colleagues*, O'Roak and colleagues** and Neale and colleagues*** which have created big headlines like this one and this one on quite a few de novo mutations - as in not present in parents but present in children - being linked to the diagnosis of autism. A fourth study picked up by Time magazine (here) by Kerin and colleagues**** on moesin adds to the flavour. This last study coincidentally being in the same publication that contains an article suggesting that the predictive power of personal genome sequencing is likely to be a little bit more limited than many initially suspected. Who'd have thought it?

Back to the Nature articles, I let the dust settle a little for two main reasons: (1) just about everyone has an opinion about this work and its meaning, and (2) my first instinct was to say 'add them to the 2193 genes, 2806 SNPs/VNTRs, 4544 copy number variations, etc' already found and discussed in relation to autism.

I've talked about mutation and genes already quite a bit on this blog and how, whether diagnosed with autism or anything else or nothing at all, we are all a product of mutation and individually carry our own store of genetic mutations. Quite by chance I just saw one of the latest Marvel film adaptations, 'Thor' complete with cameo performance from the magnificent Stan Lee, who has whether knowingly or not, popularised mutation and in some respects relieved it of its quite negative connotations. After all, every kid wants to be Wolverine or Spiderman don't they?

Anyway a very, very short summary of the papers in question:

• Sanders and colleagues* discussed exome sequencing for nearly a thousand individuals, including 200 people with a diagnosis of autism. Exome sequencing, I am reliably informed, relates to the analysis of exons, the parts of DNA which get translated into functional proteins. There is quite a good background description here. Their results identified several de novo mutations in brain-expressed genes to be present, with one mutation in the same gene present in 2 unrelated participants with autism but not in asymptomatic controls among other findings.
• O'Roak and colleagues** carried out similar exome analysis for a couple of hundred parent - child trios (trios implying mum, dad and child with autism, N=677). Their analysis suggested quite a few of the 248 de novo mutations, 126 classified as 'severely disruptive', they found were paternal in origin - from dads - and showed a positive correlation with paternal age consistent with other work on older dads perhaps being a risk factor for autism. I was interested in some elements of the last sentence of this paper abstract which talked about 'extreme locus heterogeneity' but at the same time providing ".. a target for future discovery, diagnostics and therapeutics". Make of that what you will.
• Neale and colleagues*** again sequenced exomes in 175 trios. They reported finding de novo mutations in less than half of their cases (46.3%) stating that ".. the overall rate of mutation is only modestly higher than the expected rate". Nevertheless, some clever proteomics work looking at how these mutation might fit together revealed some interesting interactions between the proteins encoded by the genes being looked at. They also suggested that carrying these mutations might up the risk of autism between 5 - 20 times compared with not having them. I was also interested in one of the gene candidates identified in this study, KATNAL2, which has been tentatively correlated with 'conscientiousness' as a personality trait (assuming you believe that personality is genetic). Dr Ben Neale, the lead author, has also summarised his team's results on a guest blog post here and done to my mind, quite a good job outside of all the hype.

I have probably not been able to do justice to the complexity and obvious work that has gone into these studies with this very short summary. There was some overlap in the genetic areas of interest across the studies which, given the statistical odds involved, might be potentially very important. I must admit that I raised an eyebrow when these papers all came out pretty much simultaneously and only a few days after the CDC reported another increase in their estimates of prevalence of autism in the United States, up from 1 in 110 to 1 in 88 8-year olds - indeed 1 in 32 boys apparently in the State of Utah. I'm sure that the timing was just coincidence though.

I've said it before and will say it again, I am not a molecular biologist or anything related, so am very much an amateur when it comes to decoding the precise meaning of exomes and de novo mutations outside of some background reading. With this in mind, I translate these collective works as suggesting a few things (but don't quote me on this):

1. The genetics of autism are getting more and more complicated with every study published. It probably doesn't help that the diagnosis of autism is a subjective experience from a clinical viewpoint and autism is often surrounded by other comorbidities which are also likely to exert an effect on results. Exactly how this might change if and when the new 'sliding scale' DSM-V autism diagnostic criteria comes out will be interesting.
2. These were studies on de novo mutations meaning that they did not originate from parents. I read one comment on a blog (here) by a commentator who drops by this blog now and again, RAJ, asking the very important question: where did all the heritability go? Does this mean that the autism of today is different from the autism of yester-year or is it all a question of technology, participant numbers, etc.?
3. How and why do these de novo mutations appear is a question that should be on everyone's lips. Random is a word that crops us time and time again in relation to these mutations but with due respect, if we are talking about these mutations showing cause and effect in relation to autism risk, saying they just randomly appear leaves quite a big gap in the knowledge base. Again with my amateur status as a caveat, I do wonder about the involvement of environment and judging by the latest blog from Tom Inset at the NIMH, I'm not the only one. The paternal spotlight and in particular the older dads suggestion from the O'Roak study has put sperm in the cross-hairs, and lets face it, that opens up a myriad of possible environmental factors outside of just 'old sperm' as potentially showing some association (something again that RAJ has commented on in other posts on this blog).
4. As per other studies on mutation in areas such as ADHD, whilst these are impressive studies utilising some impressive technologies, one perhaps needs to ask how common these mutations were in terms of autism as a whole. Yes, there were some interesting areas coming to light and yes, these should be priorities for future studies. As the paper from Neale and colleagues reported however, the overall rate of mutation was only marginally higher than what would be normally expected and one should perhaps not discount the influence of things like intellectual disability as accounting for at least some results (see here).

With the onset of epigenetics (changes to gene expression without changes to the genome), things are changing in the world of genetics. Autism research at the same time continues its fascination with this area of endeavour. The concept of an 'autism gene' covering everyone with autism (and the BAP?) is a distant memory (as are the millions of pounds/dollars/other currency pumped into this area down the years) to be replaced by an altogether more complicated picture emerging of spontaneous mutations, differing genetic profiles for individuals and genes and environment potentially acting variably but synergistically.

To finish, the UK is awash with Britain's Got Talent at the moment, and aside from asking 'where me keys, where me phone' a group called the Zimmers got me reminiscing about an old Beastie Boys classic... fight for your right to [fill in the blank].

* Sanders SJ. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. April 2012.
DOI: 10.1038/nature10945

** O’Roak BJ. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. April 2012.
DOI: 10.1038/nature10989

*** Neale BM. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. April 2012.
DOI: 10.1038/nature11011

**** Kerin T. et al. A noncoding RNA antisense to moesin at 5p14.1 in autism. Science Translational Medicine. April 2012.
DOI: 10.1126/scitranslmed.3003479

Grandparental age and future generation risk

Most people with an interest in autism research will, at some point, have heard about the proposed equation: increasing paternal age = greater risk of autism diagnosis in offspring. I say 'equation', but unlike most mathematical and statistical formulae, the 'certainty' of the advancing parental age hypothesis of autism is actually not as certain as one might have been led to believe from papers like that included in the recent Nature series. Risk is risk not certainty.

On one of the sister/brother/sibling(?) blogs to this one, I linked to a study published last summer (2010) by Golding and colleagues*. The data derived from the ALSPAC study, suggested that parental (paternal and maternal) age effects whilst potentially important to autism might actually be secondary to age effects going further back a generation. In particular grandmother's age came under the spotlight and the revelation that Grandmum's who were over 35 years old at conception/birth of mums of children with autism might be over-represented in the cases of autism identified during the ALSPAC study.

Golding and colleagues were very cautious about their findings and provided some limited speculation of how the 'meiotic mismatch methylation (3M) hypothesis' might come into play. I can't claim to fully understand all of the 3M hypothesis but risk alleles, DNA methylation and the subsequent skipping of a generation are the watchwords. Speculative but interesting.

A more recent study has also emerged discussing similar concepts as potentially being relevant to schizophrenia. The paper by Frans and colleagues** based on another very substantial cohort number suggested again that older dads (particularly those above 55 years of age) were associated with an increased risk of offspring developing schizophrenia. They also found that older maternal grandfathers age (at conception of mums) might be associated with an increased risk of schizophrenia. The authors reason some involvement of the X chromosome 'differentially' being involved.

Whilst I am in no way suggesting that autism and schizophrenia are one and the same, and bearing in mind the multitude of factors, variables and biases inherent to this kind of cross-linking work, I do find it interesting that another set of commonalities might be coming to the research surface. Quite a lot is being made about SNPs, CNVs and such like in research examining developmental, behavioural and psychiatrically-defined conditions but little has been so far offered about how and why such point mutations, deletions and insertions might come about. Yes, they may be spontaneous, they may be age-related and potentially even evolutionary but what is/are the underlying process(es)?

What these collected research suggest is that generationally, there may be good reason to start looking back at extended family as and when possible for some of the genetic clues to conditions like autism. I know that in some cases this might not be possible, but given that autism is a condition manifesting in early childhood, there are good odds that grandparents and beyond might still be around. I hasten to add that I am not talking about looking for any 'eccentric grandfathers' or anything behaviourally-defined at this point following the slew of speculation asking questions like did this person or that person have autism or Asperger syndrome. Rather asking some sensible questions about how things like age at conception and the possibility that other environmental factors which parents, grandparents (and even great grandparents) were brought up in and exposed to might have the propensity to affect the genetic make-up of subsequent generations. Bear in mind also that just because we have only fairly recently been able to catalogue such genetic features in lots of different conditions and asymptomy, does not mean that they haven't been around mutating, adding and subtracting themselves, for whatever reason, for an awful lot longer.

Just in case you need to visualise how generational research could be done, have a look at this paper from a few years back..

* Golding J. et al. Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study. PLoS ONE. April 2010.
** Frans EM. et al. Advanced parental and grandparental age and schizophrenia: a three-generation perspective. Schizophrenia Research. October 2011.

Increasing parental age and autism

I am trying to pitch at two proverbial birds with this stone of an entry. The title is quite ambiguous on purpose in that I am discussing both the suggestion of a link between advancing parental age at conception and 'risk of autism' but also the very important issue of aging parents and the provision of care for their children with autism. We will see how successfully this dual task is accomplished.

Reading through the research literature of 'risk factors' for autism, one thing outside of the sex ratio thing seems to crop up time and time again - how old parents were at the time of conception. In these times of more people having children later in life (the owness, rightly or wrongly, seemingly falling more on women than men), there is quite a lot of interest in what effects this may or may not be having on children born under such circumstances.

Whether it is mum's age or dad's age, several pieces of research have indicated a role of advancing parental years and later health and developmental outcomes. This quite large study for example, suggested that children of older dads did slightly worse on various cognitive measures compared to younger dads. Indeed, father's age has been the most interesting area when it comes to risk and conditions like autism - dare I say very strong evidence that crosses different populations?

At this point I think we have to be quite careful and remember my mantra about probability (not absolutes) and science. Yes, the results confirm a strong trend; but this by no means implies that every man in his late 40's+ fathering a child is 'predestining' that child towards autism. There are lots of other factors to consider, not least genetic influences, environment, etc; lest we start going back to the parental blame-game of times gone by.

The proposed mechanism for older dads and autism? Well there are several theories, many of which are explored on this blogsite, including methylation of DNA (something covered in my previous post on MTHFR), point mutations (SNPs), environmental factors, etc. It may be that other 'knock-on' factors such as low birth weight also come into play. Interestingly also, the calculations on what contribution older dads (and mums) have had to the rise in autism prevalence (at least in California) is not estimated to be massive. The bottom line: being an older dad carries a statistically significant association with childhood autism but lots of other factors are also potentially involved.

So then to the issue of aging parents and provisions of care for their children. This is a real issue and in years to come will, no doubt, become even more of an issue. Many parents have asked quite publicly 'what will happen to my child when I am old or when I am gone'?

Whilst appreciating that autism is a spectrum and that there are different types of presentation and different ability patterns within that spectrum, the issues of 'concern' and 'care' is pretty much a universal one given that even those at the high-functioning end of the spectrum have parents who still want to ensure the best for their child.

Many parents have blogged about this - one example is here. I read this entry and found it raised several important issues. Questions about a role for siblings in 'taking the reins'; questions about a role for 'social care'; and a very uncomfortable question about mortality. Although not by any means the same thing, similar questions have been asked about lots of other conditions not generally affecting life duration. There are no easy answers to this issue.

Assuming that there are siblings, one might expect them to take some "responsibility" if required, may be even assuming some kind of guardianship role where informed consent may not be easily given by a person with autism for example. Siblings are in a unique position because not only do they get an up-close look at autism, they follow the growth of their brother/sister and hence know more about them as a consequence.

The added benefit also being that siblings will have the best interests of their brother/sister at heart from a personal perspective rather than a social or financial ("what can the State afford") perspective. As this scenario becomes more of a reality, I expect to see many more brothers and sisters of people with autism becoming more vocal about such issues.

Some parents have talked about drawing up a personal plan of care of their child. Others have discussed drawing up wills and planning for the financial future of their child (which itself can have implications for benefits, etc). Planning seems all important to ensure that parental wishes are at least indicated.