Even more air pollution and autism risk findings

Air pollution.

I'm pretty sure most people are aware of all the talk about air pollution these days and how the human body is not particularly fond of air pollution in terms of potential adverse health outcomes (assuming that is, you leave things like selenium out of the equation). If you happen to live in China, I'm sure your mind was put at ease when reading about 'The Five Surprising Gains from the Smog'... or maybe not.

Most people generally find it easier to accept that air pollution might show a possible connection with something like respiratory diseases for example, given that the airways are generally a first point of entry for said pollution getting access to the body (although not the only route). Mention that something like autism risk for example, might also be linked to air pollution exposure and I'm sure that a significant degree of eye-rolling begins, alongside mutterings of the old 'correlation is not the same as causation' argument.

The Alchemist @ Wikipedia 

Personally I'm quite intrigued by the results emerging looking at something like childhood or maternal exposure to air pollution and proximity to sources of air pollution being linked to child or offspring autism risk. In these times of the autisms and various external forces implicated in autism risk (think valproate for example and the recent special reminder from the MHRA on this matter; even someone mentioning the word 'proven' [1] as if such a thing exists) I don't think we can rule most things out yet.

You have for example, the data from Heather Volk and colleagues [2] which was talked about in this post compounded by the data from Tracy Ann Becerra and colleagues [3] (see this post) both quite recently pinpointing something of a statistical association at least. That and other studies looking at a possible association.

Enter then another study by Volk and colleagues [4] which adds another layer of intrigue and complexity to the air pollution link by suggesting that a certain kind of genotype combined with air pollution exposure might elevate the risk of autism. There has been some media coverage of this paper (see here).

I suppose the first thing to take from the latest Volk paper is it's concentration on gene x environment interactions potentially modifying the risk of something like autism. I'm sure readers are used to hearing about [variable] gene-environment interactions quite loudly proclaimed these days as accounting for the presence of autism, but to see a study looking experimentally at the issue is very refreshing.

The next thing to note about the Volk paper is the specific focus on the MET receptor tyrosine kinase (MET) gene and a particular version of this gene potentially interacting with something like air pollution. In the post titled: 'I'm glad I MET you' (no prizes for the headline there) I talked about some other rather interesting findings when it came to MET and autism. Alongside all the chatter about things like synaptic development which MET has been tied to [5] was the suggestion that "the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003)" as per the paper from Heuer and colleagues [6]. Maternal autoantibodies, as regular readers might know, are an upcoming area with autism risk in mind (see here).

It is then perhaps no surprise that the MET rs1858830 genotype, same as that one looked at with maternal autoantibodies in mind, was also the focus on the recent Volk paper and in particular the 'CC' genotype (see here for some information on zygosity). This genotype seems to be one which is more commonly noted in relation to cases of autism [7]. Indeed, based on an analysis of participants involved with the CHARGE initiative (beincharge!) the authors suggested: "Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures". Big words, I'm sure you'll agree.

These results are obviously crying out for replication for starters. The focus of this study was (a) on one gene, one specific variant of one gene, in our entire genome (b) looking at structural issues with said gene not necessarily gene function as per that rising star which is epigenetics for example might have on gene expression, and (c) based on air pollution exposure estimates from "local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone)". With those factors in mind, caution still needs to be applied to these results before anyone goes and tries to for example, market any sort of genetic test for air pollution related autism or anything similar... Oh and 'steering clear of cities' is probably not a realistic option for most people either. Indeed, even residing in the countryside has been linked to autism risk (see here).

But still I'm interested in these results and indeed, the next question of biological processes from genes to environment to development and behaviour.

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[1] Harden CL. In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven. Epilepsy Currents 2013; November/December 2013: 13; 282-284.

[2] Volk HE. et al. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013 Jan;70(1):71-7.

[3] Becerra TA. et al. Ambient air pollution and autism in Los Angeles county, California. Environ Health Perspect. 2013 Mar;121(3):380-6.

[4] Volk HE. et al. Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology. 2013 Nov 14.

[5] Judson MC. et al. A new synaptic player leading to autism risk: Met receptor tyrosine kinase. J Neurodev Disord. 2011 Sep;3(3):282-92.

[6] Heuer L. et al. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry. 2011 Oct 18;1:e48. doi: 10.1038/tp.2011.48.

[7] Jackson PB. et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2009 Aug;2(4):232-6. doi: 10.1002/aur.87.

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Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, & Campbell DB (2013). Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology (Cambridge, Mass.) PMID: 24240654

Autism, the autisms or "developmental brain dysfunction"?

"If you've met one person with autism, you've met one person with autism" so the oft-cited phrase goes.

The implication is that whilst unified under the label of presenting with the triad/dyad characteristics of an autism spectrum condition, the heterogeneity present across the spectrum coupled with other comorbidity, allied to factors such as genes, personality, temperament, maturation, environment et al, mean that everyone is different and importantly everyone is dynamic.

Umbrella under an umbrella? @ Wikipedia  

Another term used by some people (including researchers) is that of 'neurotypical'  to somehow denote not-autism. For me however, that's always been a little too simplistic. It implied (a) that there is a definite line between autism and not-autism which kinda over-simplifies things including the broader autism phenotype (BAP), and (b) that there is such as thing as 'neurotypical' and indeed is counter to the phrase: 'if you've met one person, you've met one person' which should surely be as pertinent to not-autism as it is to autism; if you get me?

These concepts are relevant as today I'm talking about two papers: a paper by Whitehouse & Stanley* (open-access) questioning whether autism is one condition or multiple conditions, and a paper by Moreno-De-Luca and colleagues** which implies that we should even be doing away with behaviourally-defined labels such as autism and schizophrenia in favour of an altogether broader definition of 'developmental brain dysfunction' or DBD.

Regular readers might recognise the name Andrew Whitehouse as being one and the same researcher who has talked about various autism-related results from the Raine study (see here and here and here). His latest opinion piece builds on the fact that despite the 70 year anniversary since the first description of autism was published by Kanner (with appropriate consideration for Hans Asperger too), alongside huge amounts of time, money and research efforts, we are really still only scratching the research surface of the condition(s) known as autism. Certainly science hasn't yet come up with many defining 'universal' reasons to account for the appearance of the the clustering of symptoms and as for intervention options, well take a look at the recent draft guidance from NICE to see what I mean. One of the main stumbling blocks he and his colleague opine on is the "phenotypic variability" and how moves should be made towards defining smaller subgroups on the autism spectrum. In effect talking about the autisms over autism as per another very interesting paper by Poot*** (open-access).

To many people this is not new news. That the search for an 'autism gene' or 'autism genetic mutation' (sorry about the cold science term) or indeed 'autism environmental variable' has so far been underwhelming in terms of results coupled to the cost/benefit ratio of such research for example, is testament to the variability present in both autism and not-autism. This demonstrates also how complex a continuum the autism spectrum is. Indeed how complex a thing the human spectrum is****.

Likewise when it comes to intervention, I've talked before on this blog about how we should perhaps be re-assessing the way we look at proposed interventions and in particular focusing on subgroup responses rather than some almighty universal spectrum response to denote intervention success of not. Without equating autism with cancer or vice-versa, the recent opinion paper by Stewart & Kurzrock***** (open-access) might inform this methodological discussion somewhat further.

Whitehouse and Stanley also talk about the lessons learned from cerebral palsy (CP) and how where once CP was thought of as "a unitary disorder", the more contemporary view is somewhat more "umbrella" like. I've covered CP on this blog before so won't say much more about that; I think many people might agree that autism is similarly an umbrella term; even more so when the DSM-V comes into force in literally weeks time (Monday 20th May 2013 apparently).

The Moreno-De-Luca paper goes one stage further. As per the paper and some associated media attention (see here) the suggestion is that not only is there the autisms, but that because of the various overlapping genetic features between the autisms and conditions such as schizophrenia (the schizophrenias), we should be looking at using an even more over-arching concept to group these collected diagnoses together: developmental brain dysfunction (DBD). A sort of umbrella for the umbrella if you like. It's not a new suggestion by the way****** (open-access).

I can imagine that your view of autism - be that a personal perspective of autism, a parental perspective or just an observer looking in - is probably going to influence how you receive this suggestion to some degree. For a researcher looking at the possibility of shared genetics or even epigenetics between conditions which might overlap, there is some sense in looking at the bigger picture. My recent post on common ground (see here) based on the 'five psychiatric disorders linked' paper******* kinda reiterates this position alongside other papers including this one from Caamaño and colleagues******** on subclinical comorbid psychopathology. That and the fact that there might be some convergence when it comes to the autism and schizophrenia spectrums for example (see here) also makes a case. The authors sum it up well: "genes don't respect our diagnostic classification boundaries, but that really isn't surprising given the overlapping symptoms and frequent co-existence of neurodevelopmental disorders".

Other perspectives - and I am only speculating on such viewpoints - might not necessarily share the same sentiments. Aside from leaving out any important relationship that genes might have with little things like the environment, as in maternal immune activation during pregnancy, or all those correlations with other facets of modern living (see here and here), the implication of 'brain dysfunction' takes us back to the whole neurotypical 'us and them' scenario and the questions: what exactly is 'normal' brain function? and what factors can and do affect it? I might add that I can also see how some people might not necessarily be taken with the concept of autism being akin to 'brain dysfunction' in the same way that lumping autism and schizophrenia together might have other, more societal connotations.

I'm going to stop there with this post, save any charges of over-analysing the papers and potential implications. Accepting that a diagnosis is currently the best way for people to [theoretically] receive the help and support they may need, I'm not sure we are in a position to re-write the diagnostic manuals just yet with autism and schizophrenia in mind. That umbrella-ing (is that a word?) autism with other conditions might also impact on the autism awareness message that we've all just had with World Autism Awareness Day is another consideration to bear in mind.

That being said, I do think we have already started to see hints of this brave new world of links and threads coming together. The DSM-V diagnosis of autism seems to be quite explicitly spectral and whilst not yet knowing the consequences of removing diagnoses such as Asperger syndrome and how that Social Communication Disorder category will work, the idea behind the change is sub-type removal similar to that envisaged for schizophrenia (see here and here). I'm not altogether sure but I am also wondering how and whether there will be any exclusion criteria on for example a dual diagnosis of autism and schizophrenia in the new guidance and what effect this might have? We wait and see.

"OK stop already". And I will.

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* Whitehouse AJO. & Stanley FJ. Is autism one or multiple disorders? Med J Aust 2013; 198: 302-303.

** Moreno-De-Luca A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. The Lancet Neurology. 2013; 12: 406-414.

*** Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Molecular Syndromology. February 2013.

**** Mitchell KJ. What is complex about complex disorders? Genome Biology. 2012; 13: 237.

***** Stewart DJ. & Kurzrock R. Fool's gold, lost treasures, and the randomized clinical trial. BMC Cancer 2013; 13: 193.

****** Hrdlicka M. & Dudova I. Controversies in autism: is a broader model of social disorders needed? Child & Adolescent Psychiatry and Mental Health 2013; 7: 9.

******* Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis The Lancet. February 2013.

******** Caamaño M. et al. Psychopathology in children and adolescents with ASD without mental retardation. JADD March 2013.

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Whitehouse AJ, & Stanley FJ (2013). Is autism one or multiple disorders? The Medical journal of Australia, 198 (6), 302-3 PMID: 23545020

Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, & Ledbetter DH (2013). Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet neurology, 12 (4), 406-14 PMID: 23518333

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

Epigenetics, EN-2 and the 'autism brain'

A paper by Jill James and colleagues* (open-access) caught my eye recently. Centred on Engrailed-2 (EN-2), a gene with more than a passing relationship to cases of autism (see here), James et al report results based on analysis of a small number of post-mortem cerebellar samples with a particular focus on an epigenetic evaluation.

Cerebellum @ Wikipedia  

What is epigenetics? Well, I've written before about some of the basic concepts involved (see here) and how despite not everyone being enamoured with the rise and rise of the science, the discipline of epigenomics adds quite a distinctive layer to the functioning of a persons genome.

The basic tenet: your DNA might not necessarily be your destiny and that subtle changes to the epigenome can influence the expression of certain genes or not. Certainly in areas such as cancer medicine, epigenetics is starting to make some real waves (see here).

With autism in mind, epigenetics is also starting to make an impact on the scientific literature and promises so much more. I'm taken for example, back to some previous work looking at prefrontal cortex neurons** with autism in mind which concluded that there might be more to see in this area at least for some cases of autism.

Anyhow....

• James and colleagues focused on cerebellar samples because (a) the cerebellum has been a real area of interest to autism research, and (b) EN-2 is "highly expressed in Purkinje cells"; reaffirming some interesting observations noted about Purkinje cells in the cerebellum of people with autism***.
• They analysed 26 samples from 13 people with autism and 13 asymptomatic controls. Details of how participants died and other details are provided in the paper, bearing in mind the various discussions on how post-mortem brain samples from those deceased who had autism are subject to various confounders including how they died and the role of any comorbidity. Incidentally, some of the autism samples originated from the same place which had that very unfortunate freezer malfunction last year (see here).
• Various methods and techniques were used to assess the details of epigenetic functions focused on methylation. I can't and won't pretend to understand all of them but interestingly as well as looking at EN-2 promoter region methylation, global methylation and "the methylation status of histones H3K27 (associated with gene silencing) and histone H3 lysine 4 (H3K4; associated with gene activation)" was also included (see here), part of the histone code.
• Results: some interesting ones such as the finding of hypermethylation of DNA extracted from autism cerebellum samples, which contrasts sharply with the DNA hypomethylation of immune cells noted by some of the authorship group on another occasion****. The authors speculate that this could be indicative of "tissue-specific" DNA methylation in autism; also noting that short of looking at brain samples - which is neither desirable or feasible for the living - we can't conclude too much from "peripheral cell DNA methylation patterns". This should make for some interesting future discussions I reckon.
• Alongside this global hypermethylation, James reports hypermethylation of the EN-2 promoter region. This, alongside sustained gene expression of EN-2 and greater levels of EN-2 protein in the autism samples. Similarly when looking at the methylation of histones (H3K27 and H3K4), the histone H3K27 which is linked to gene suppression was decreased and the histone H3K4 linked to gene activation, was increased (albeit not significantly).
• Assuming that I've understood this all correctly, the suggestion is that epigenetic issues with the histones involved in gene suppression or gene activation (via methylation) were congruent with a pattern of "sustained EN-2" gene over-expression which might tie into the loss of Purkinje cells***** noted in the cerebellum of some people with autism. At least I think so.

It all makes for some really rather interesting findings. That for example, the modification of histones ties into the levels of gene expression and importantly gene protein levels is really exciting and perhaps a valuable addition to the notion that mutation in the form of SNPs are the only influencing variable on gene function. Indeed that an epigenetic process might affect the timing of gene activation/suppression at critical periods of development is also an important point bearing in mind that we don't all walk around with all our genes permanently stuck in the 'on' position.

One also starts to wonder about not just the availability of methyl groups in this process but also the functioning of things like the DNA methyltransferase enzyme family (adding methyl groups) and indeed the demethylase enzymes (removing methyl groups) and the circumstances of their control at certain periods of development. Indeed methylation is only one facet of histone modification, as per the acetlyation and deacteylation of histone which potentially brings us back to things like the valproate connection being made to cases of autism (see here). It's all quite complicated.

Perhaps just as important are the implications of hypermethylation and those histone modifications to other genes tied into things like neuronal development and immune function in conditions like autism. Noting for example the Saxena paper (covered here) and their linking quite a few of the autism-related genes to things like immune function, James and colleagues make mention of one demethylase, JMJD3 (see here) and its potential link to the "IL-6 gene promoter" with regards to processes such as neuroinflammation. Certainly one has to ponder how deep the rabbit hole goes.

OK, coming back down to earth, caution is required in that this was a relatively small scale study which is again, always going to be confounded by the use of post-mortem brain samples and factors such as cause of death and the important point that autism is a behavioural label and that link of possible heightened comorbidity. Added to the fact that the focus was on one particular gene - one of quite a few - with some apparent connection to autism, the results should be viewed as preliminary at best.

That being said, we have a template now for expanding this area of work to cover other candidate genes in different tissues, to start working on those all-important rodent models. Then, with some degree of caution and assuming a strong connection is made, looking at the various factors which might potentially influence and moderate such epigenetic issues - including sex differences****** (open-access) - bearing mind the golden concept of phenotypes.

This could be something quite big...

Speaking of big (famous), they don't come much bigger than this lady....

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* James SJ. et al. Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Translational Psychiatry. 2013: 3; e232.

** Shulha HP. et al. Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry. 2012; 69: 314-324.

*** Fatemi SH. et al. Purkinje cell size is reduced in cerebellum of patients with autism. Cell Mol Neurobiol. 2002; 22: 171-175.

**** Melnyk S. et al. Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J Autism Dev Disord. 2012; 42: 367-377.

***** Baader SL. et al. Ectopic overexpression of engrailed-2 in cerebellar Purkinje cells causes restricted cell loss and retarded external germinal layer development at lobule junctions. J Neurosci. 1998; 18: 1763-1773.

****** McCarthy MM. et al. The epigenetics of sex differences in the brain. J Neurosci. 2009; 29: 12815-12823.

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James SJ, Shpyleva S, Melnyk S, Pavliv O, & Pogribny IP (2013). Complex epigenetic regulation of Engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Translational psychiatry, 3 PMID: 23423141

Metallomics analysis and autism

As an avid follower of several of the -omics, I was interested to read the report by Hiroshi Yasuda and colleagues* (open-access) on the application of a new -omics to me, metallomics - think metals affecting cellular functions - and in particular, the application of metallomics to autism.

This is not the first time that the work of Hiroshi Yasuda has appeared on this blog, as per my previous entry on 'the link with zinc' highlighting some interesting findings of zinc deficiency in quite a sizable proportion of their cohort diagnosed with an autism spectrum disorder (ASD).

Mick's home or 'ome Mick's? @ Wikipedia  

The autism metallome?

Yasuda's latest paper - published in the same Nature family journal, Scientific Reports - extend their analysis of the metals outside of just zinc to include quite a few more and likewise report on what looks like the same cohort of participants as their previous paper.

A few details bearing in mind the paper is open-access:

• Quite a big cohort (N=1967) of Japanese children diagnosed with an ASD were included for study.
• Hair samples taken from as close to the scalp as possible (I assume denoting a more current metallomic profile) were analysed by everyone's favourite metal analysis technique, ICP-MS. I might add that not everyone is convinced that hair analysis is a great way of testing for metal status or anything else. 
• Results: well we know that zinc levels were already reported on the low side; indeed a zinc deficiency was present in over 40% of the 0-3 years age group (43%), getting a little better as the age ranges increased: 4-9 year olds (28%) and 10-15 year olds (3%) in males (who comprised most of the cohort). Females also showed a similar pattern across the age ranges (52%, 28%, 3% respectively).
• Magnesium and calcium deficiency were also highlighted as being present among a proportion of their cohort; albeit not to the same extent of the rates of zinc deficiency.
• A quote: "high toxic metal burden of aluminium, cadmium and lead of over their +2 S.D. level was observed in 339 (17.2%), 168 (8.5%) and 94 (4.8%) individuals".
• A few examples are given showing the metallome of individual participants which seem to lead to an interesting suggestion that zinc deficiency (together with magnesium deficiency) might correlate somehow with a "high toxic metal burden".

Link with zinc

I'm not going to offer too much in the way of discussion about the zinc part of these results given my past reporting on the previous paper** by Yasuda et al alongside some background on zinc. A few additions perhaps are worthy of mention in light of the suggestion of an epigenetic role of zinc deficiency. Regular readers will already know that I'm getting quite enamoured with the whole 'your genome is not your destiny' revolution that seems to be occurring these days. I note for example the paper by Kurita and colleagues*** which in a mouse model at least, points to a possible epigenetic effect from zinc deficiency occurring in-utero. The assumption being that especially in that 0-3 age group where zinc deficiency was highest in the Yasuda study, gestational zinc deficiency might have preceded infantile deficiency? And then there's the whole inflammation side of things as per the paper by Wessels and colleagues**** bearing in mind what we call inflammation and also infection (see here).

Magnesium

The rates of magnesium deficiency were also quite striking in their Japanese cohort. I assume most people with some interest in autism will know all about the whole vitamin B6-magnesium connection stretching back some years now. Granted the evidence base looking for example, at supplementation with B6 and magnesium is still a little incomplete as per the Cochrane review from Nye and Brice***** but I would also draw your attention to some interesting studies in the decade of big hair and electro-pop (the 80's) by Lelord and colleagues******* (who are also credited with devising the rather nice Behaviour Summarised Evaluation Schedule). I might add that this is not the first time that magnesium deficiency has been reported in cases of autism, illustrated by the papers by Wecker and colleagues******** and Lakshmi and Geetha*********, although not universally so. The causes and effects of such deficiency? Well, lets just say that I have a few ideas outside of just faddy diets affecting intake but I'm not fooling myself that this process would be so simple and universal.

Calcium

As for the other findings, well, let's just say that I've done lead before (see here) so I'm not heading down that path again. Calcium deficiency is something that I am quite interested in as a result of the use of things like a casein-free diet as a possible intervention measure for some cases of autism. As discussed in other posts, calcium seems to have its own relationship to some cases of autism and especially the view that such dietary intervention might impact on calcium levels. Indeed calcium intake is known to often be a little lower in cases of autism*********. That being said, I'll also draw your attention to some other recent literature on the calcium-autism link (see here) and on whether or not the sunshine vitamin might also play some role in this complex relationship.

Yasuda and colleagues conclude their paper by talking about the possibility of "a critical term “infantile window” in neurodevelopment and for its therapy" in light of the deficiencies and elevations they found. I'm not sure that we are quite there yet so as to be able to suggest that supplementing with zinc or magnesium or calcium during the very earliest days is somehow able to mitigate the risk of autism onset. Certainly I'd be wary of seeing anyone make any general recommendations on such supplementation strategies during such early development without both confirmatory evidence of deficiency in specific cases (including whether seasonality might for example affect results**********) and some further safety work looking at optimal dosage and delivery. Oh, and a good explanation as to why the deficiency was there in the first place might also be a good idea...

To finish and to celebrate Rolf Harris continuing to wow audiences, a classic... Jake the Peg (with his extra leg).

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* Yasuda H. et al. Estimation of autistic children by metallomics analysis. Sci Rep. 2013; 3: 1199.

** Yasuda H. et al. Infantile zinc deficiency: association with autism spectrum disorders. Sci Rep. 2011; 1: 129.

*** Kurita H. et al. Prenatal zinc deficiency-dependent epigenetic alterations of mouse metallothionein-2 gene. J Nutr Biochem. 2013; 24: 256-266.

**** Wessels I. et al. Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms. J Nutr Biochem. 2013; 24: 289-297.

***** Nye C. & Brice A. Combined vitamin B6-magnesium treatment in autism spectrum disorder. Cochrane Database Syst Rev. 2005; 4: CD003497.

****** Lelord G. et al. Clinical and biological effects of high doses of vitamin B6 and magnesium on autistic children. Acta Vitaminol Enzymol. 1982; 4: 27-44.

******* Wecker L. et al. Trace element concentrations in hair from autistic children. J Ment Defic Res. 1985; 29: 15-22.

******** Lakshmi P. & Geetha A. Level of trace elements (copper, zinc, magnesium and selenium) and toxic elements (lead and mercury) in the hair and nail of children with autism. Biol Trace Elem Res. 2011; 142: 148-158.

********* Sharp WG. et al. Feeding problems and nutrient intake in children with autism spectrum disorders: a meta-analysis and comprehensive review of the literature. J Autism Dev Disord. February 2013.

********** Teresa M. et al. Trace element concentrations in blood and hair of young apprentices of a technical-professional school. Sci Total Environ. 1997; 205: 189-199.

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Yasuda H, Kobayashi M, Yasuda Y, & Tsutsui T (2013). Estimation of autistic children by metallomics analysis. Scientific reports, 3 PMID: 23383369

The focus is on autism

This is one of my more 'advertorial' posts I'm afraid, as I bring to your attention two important special supplements on autism published in two high-profile journals.

The first is yet another open-access special edition published in Nature (see link here), which complements their previous special edition from this time last year (2011). I'm impressed it has to be said, that Nature would choose to return to autism two years running, which really does tell you how much scientific and lay interest there is about the condition.

As to content, lots of interesting views and opinions but a few highlights to mention:

• Well it's nice to see that epigenetics (there's so much more to the genome) gets a mention as per this article by Sarah Williams*. The possible usefulness of systems biology is also discussed, albeit with more of slant on proteomics over my favourite, metabolomics. 
• Michael Eisenstein** talks pharmacotherapy which includes quite a bit about Fragile X syndrome chatter and all those glutamate-targeting advances (see here) which potentially offer so much. My attention however was more focused on the preliminary results from administration of N-acetlycysteine (NAC) in cases of autism and even some suggestion that the immune-inflammatory link to some cases of autism might be a target for therapy, and quite unconventional - helminthic - therapy at that. 
• Of course one cannot talk about autism nowadays with making some reference to DSM-V as per the article by Emily Singer*** which complements/is complemented by a recent piece by Jon Brock elsewhere.

The second special edition / supplement graces the journal Pediatrics, and a whole slew of articles on autism (see link here). Regular readers of this blog (hello, anyone there...) will have already been given a heads-up for one of the articles published as part of the Pediatrics supplement by a cracking group of researchers, all discussing gastrointestinal (GI) factors and autism (see here).

Some more interesting tidbits for your, pardon the pun, digestion:

• Perrin and colleagues**** discuss the use of complementary and alternative medicine (CAM) in autism. As someone who does not necessarily see dietary intervention as being anything like CAM - remember Hippocrates 'Let food be thy medicine' - it's nevertheless interesting to read about how CAM use seems to be more widespread among those children whose autism is present alongside other comorbidites such as GI problems and seizure disorders. I hate to use the term ' the bleeding obvious' but it does kinda stand to reason that GI issues might persuade someone to look at diet for example, as being a potential player to those issues. Or maybe it's just me? I note also that Dr Susan Hyman is among the authorship group to this paper, which got me wondering about the status of that gluten- and casein-free diet study that she was undertaking which still appears on the ClinicalTrials.gov website, albeit 'status unknown'. 
• Sikora and colleagues***** report some really interesting results based on what happens when ADHD and autism are comorbid. Again, probably not something completely unexpected in that quality of life is not great, or at least not as great as when ADHD symptoms are not present. If ever there was another example that comorbidity can be (a) present and (b) a real challenge for people with autism, here it is.
• Beth Malow and colleagues****** describe a potentially very informative tool, an insomnia practice pathway to help identify such issues in cases of autism. So, screening taking into account other medical factors, discussing various therapies which does not necessarily just mean introduce melatonin, and an important one here, follow-up and "evaluate effectiveness and tolerance of the therapy". It all sounds great in principle, but again I'm just going back to the 2010 Pediatrics guidance on GI conditions and autism******* and wonder how successful such best-laid plans turn out to be in practice.
• Final one, Ann Reynolds and colleagues******** talk iron and autism (as I have previously done on this blog) and report that issues with the availability of iron might not actually be all that widespread in autism after all. By saying this, I'm not taking away anything from the cases where iron availability is an issue. 

There is plenty of bedtime reading there for everyone and importantly, an ideal vehicle for keeping autism and autism research in the public consciousness. To close, a song that I think everyone would welcome, young and old, either first thing in the morning or last thing at night...

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* Williams SCP. Genetics: searching for answers. Nature. 2012; 491: S4-S6.

** Eisenstein M. Treatments: in the waiting room. Nature. 2012; 491: S14-S16.

*** Singer E. Diagnosis: redefining autism. Nature. 2012; 491: S12-S13.

**** Perrin JM. et al. Complementary and alternative medicine use in a large pediatric autism sample. Pediatrics. 2012; 130: S77-S82.

***** Sikora DM. et al. Attention-Deficit/Hyperactivity Disorder Symptoms, adaptive functioning, and quality of life in children with autism spectrum disorder. Pediatrics. 2012; 130: S91-S97.

****** Malow BA. et al. A practice pathway for the identification, evaluation, and management of insomnia in children and adolescents With autism spectrum disorders. Pediatrics. 2012; 130: S106-S124.

******* Buie T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125 Suppl 1:S1-18.

******** Reynolds A. et al. Iron Status in Children With Autism Spectrum Disorder. Pediatrics. 2012; 130: S154-S159.

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Autism: the sum of its SNPs?

I chanced upon a new piece of research published by Lambertus Klei and colleagues* (open-access) on single nucleotide polymorphisms (SNPs) and autism, and how lots of little mutations might additively contribute to increasing autism risk.

Calculate this @ Wikipedia 

OK, stop.. hammertime.. a few descriptions and details are needed first as well as a caveat about my amateur status when it comes to all things genetics.

SNPs and mutations. A short description is included here but basically think small changes to the letters of the genetic code. Suffice to say that I've covered SNPs and those copy number variations (CNVs) and autism on more than one occasion on this blog as per posts like this one on no single SNP being associated with the universality that is the autism label and this one on just how complex autism seems to be from a genetics perspective.

I hope I've not been too unkind to genetic mutation research (sorry for the cold science term) specifically with autism in mind, but like other developmental conditions such as attention-deficit hyperactivity disorder (ADHD), the whole 'genetics is absolute ruler' argument has not been borne out by the data produced so far. Each and every one of us, whether diagnosed with autism or anything else, are the product of mutation and autism is a mighty diverse condition.

With all this in mind, the Klei paper whilst open-access has a few interesting points worth noting:

• This was a study aiming to look at a few important issues. Not only the question of simplex (one child) vs. multiplex (more than one child) genetic risk of autism and whether they might be different, but whether despite not one SNP being universally applied across all autism, there may be some argument for more [important] SNPs cumulatively = a greater risk of autism.
• Based on genotype data derived from two autism-related datasets representing simplex and multiplex families respectively, the Simons Simplex Collection (SSC) and the Autism Genome Project (AGP), comparisons were made with control data (HealthABC) across several hundred thousands of SNPs for something called narrow-sense heritability - in effect additive genetic variance. There was also a further test group used to assess the robustness of findings (Neurogenetics Research Consortium, N=1986).
• Results: "For simplex families, who have only a single affected individual in multiple generations, approximately 40% of liability traces to additive effects whereas this narrow-sense heritability exceeds 60% for ASD individuals from multiplex families". The actual results were: simplex (39.6%) and multiplex (65.5%); this last figure reflective of the AGP cohort splitting, with some simplex and some multiplex families included; simplex heritability in the AGP group being estimated at 49.8%. These estimates also bearing in mind the "unrealized multiplex potential" of taking snapshots of families.
• Another result: "These results suggest that AGP parents carry a greater load of additive risk variants than SSC parents and thus are, on average, closer to the threshold of being affected". Translation: parents of participants in the AGP cohort, bearing in mind this included both simplex and multiplex families, showed more additive risk SNPs and hence were closer to the diagnosis of autism or the broader phenotype than in the SSC cohort taking into account differences in screening for autism in parents between the two cohorts.
• And another result: "A curious observation from AGP multiplex families was that fathers generate larger heritability than mothers". Translation: lots of potential reasons for it (including the issue of mums, dads and differing proportions of sex hormones) but dads seemed to generate more 'risk' than mums in multiplex autism.
• And a final result: "Our results suggest that common variants affecting liability do not cluster on chromosome X". An interesting observation given the focus on the X chromosome as a result of the reported male domination of autism.
• Mention is also made of assortative mating as being involved in the results but as yet no new data is presented on this possibility.

I like the quote from one of the chief authors on the paper, Prof. Bernie Devlin reported here: "The genetic components alone are far more complex than many imagined a decade ago, including the additive effects we have found, rare inherited mutations, and new mutations arising spontaneously before conception." To me this embodies everything about the current state of knowledge on the genetics of autism in that (a) there is probably no universal 'autism' gene, (b) mutations are likely to be an important part of autism risk and (c) new mutations opens the door up to environment as playing a hand (spontaneous eh?). Indeed the only thing missing from this sentence is discussion about the relative newcomer, epigenetics, and how looking at the function of genes might be able to plug some of that gap in the risk for developing autism.

As per my recent post on systems biology and autism, one also has to ask whether there might be some common biochemical pathways to be derived from these additive genetic effects. Not so long ago, Skafidas and colleagues** were discussing SNPs in relation to gene and biochemical functions, with some interesting observations detailed (see this post). I'd be very interested to see what might come from similar analyses on the Klei data and whether there is overlap or differences based on simplex or multiplex cases.

Whilst an interesting paper, there still remains some significant holes in our knowledge about autism and the risk factors for receiving a diagnosis of autism. Those 40% and 60% risk figures are probably what many people are going to focus on, but my question is what about the remaining 60% or 40% of risk and indeed the question of 'where did the heritability go?' based on previous twin studies lining the autism research trail (see here). Where does that risk come from? and should we perhaps be looking at environmental factors with as much assiduity as we do genetic ones?

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* Klei L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism. 2012; 3: 9. doi:10.1186/2040-2392-3-9

** Skafidas E. et al. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis Molecular Psychiatry. September 2012; DOI: 10.1038/mp.2012.126

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Klei, L., Sanders, S., Murtha, M., Hus, V., Lowe, J., Willsey, A., Moreno-De-Luca, D., Yu, T., Fombonne, E., Geschwind, D., Grice, D., Ledbetter, D., Lord, C., Mane, S., Lese Martin, C., Martin, D., Morrow, E., Walsh, C., Melhem, N., Chaste, P., Sutcliffe, J., State, M., Cook, E., Roeder, K., & Devlin, B. (2012). Common genetic variants, acting additively, are a major source of risk for autism Molecular Autism, 3 (1) DOI: 10.1186/2040-2392-3-9

A systems biology approach to autism

I might have mentioned it before but quite a bit of my interest on this blog and its sibling blogs outside of the behemoth that is autism research is dedicated to several of the -omics disciplines. Omics? What on earth is he talking about? Well, think genomics (the study of the genome) and extend it to other areas of investigation such as:

Lots of leads? @ Wikipedia 

• the microbiome (microbiomics - the study of bacteria, or more specifically, the bacteria that inhabit us), 
• the epigenome (epigenomics - the study of the various ways in which gene function can be modified or altered), 
• and the metabolome (metabolomics - the study of the low molecular weight metabolites that we all produce [and excrete] on a daily basis).

If I had to 'pick an omic' (now there's a new saying) that I perhaps have had most experience with, it would have to be metabolomics and the whole biomarker thing based on some of the technology and work I've been involved with (albeit not as lead). Indeed metabolomics, whilst sounding very, very complicated is actually quite a simple science in terms of its basic tenets: chemically separate sample, chemically analyse sample, statistically analyse results, organise statistical results. It obviously gets a little more complicated as you delve further into the technology (mass spectrometry, nuclear magnetic resonance) and the statistical methods (principal components analysis) involved, culminating in literally volumes of data.

Another layer to the whole metabolomics (and other -omics) field is the area of systems biology (and bioinformatics). Although quite a nebulous term, systems biology can involve back-tracking through your metabolites of interest in order to both look at interactions between the metabolites and eventually from which systems they derive and whether there is a connection between those systems. It's data organisation for biology. A good example of the process was demonstrated in a recent post on carnitine and autism (bearing in mind this was more of a proteomics kinda thing).

'Get to the point' I hear you cry, as I bring to your attention a paper by Randolph-Gips & Srinivasan* (open-access) discussing the modelling of autism with a systems biology slant. The first thing to say about this paper is that whilst no new data is actually presented, it represents a pretty good review of the complexity of autism based on quite a lot of the more biochemical research undertaken. So for example the key areas of antioxidant, gastrointestinal, mitochondrial, immunological and neurological functions are included alongside a whopping 183 references; someone has done an awful lot of background reading for this paper. The value-added bit to the paper (IMHO) is the suggestion that modelling the variety of presentations in these various areas in cases of autism might actually be quite a useful thing to do.

I wouldn't claim to be an expert on systems biology but do recognise some of the suggestions mentioned in this paper. So things like hierarchical modelling and identifying subgroups (yes, endophenotypes again). Also taking into consideration that autism is not a static entity (the authors refer to autism as a 'disease' but I would disagree with that description) and the introduction of things like dynamic time warping to take maturational changes for example, into account.

I know some people won't be convinced by papers like this. They'll either question the various research included in the review and its relevance to autism, or point out the volumes of research missing from the review. I agree that this is a complex area; autism research, the thousands and thousands of findings reported on the autisms over the years, is complicated. The point of papers like this however is how we go about organising all that knowledge into something manageable, responsive to the addition of new data and useful in terms of discerning the various connections between often disparate areas of research onward to hypothesis generation. Realising also that although research findings may be presented with autism in mind, does not mean that they aren't also relevant to other conditions (and indeed possible comorbidities) is an important part of this systems biology approach.

Now all we need is someone to put some money and time into building that massive database or indeed incorporating new knowledge into existing databases. Any takers?

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Randolph-Gips MM, Srinivasan P. Modeling autism: a systems biology approach. J Clin Bioinforma. 2012; 2: 17.

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Randolph-Gips MM, & Srinivasan P (2012). Modeling autism: a systems biology approach. Journal of clinical bioinformatics, 2 (1) PMID: 23043674

PCB congeners and 15q11-q13 duplication autism

Contains PCBs @ Wikipedia

The science news is currently awash with talk about results from the Encyclopedia of DNA Elements (ENCODE) project (see here for a good description). The net results have been summarised by quite a few media outlets including the BBC, including the suggestion that junk DNA might not be as junk as first thought (see this post from MJ over at Autism Jabberwocky).

I was interested to see that the words DNA methylation cropped up quite a few times during the course of the various discussions, and how the switching on and off of genes might actually be pretty important to our lives. It all got me thinking back to everyone's favourite gene-environment science, epigenetics (see here).

With all this in mind, a recent paper by Mitchell and colleagues* provides some food for thought. Including a significant authorship contingent from that autism research favourite, the MIND Institute, the paper abstract makes a striking assertion: "These results demonstrate a novel paradigm by which specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13".

I admit that I did a bit of a double-take when I read this sentence given that it seems to suggest some involvement of POPs in what is a genetic condition.

OK let's just back it up a little and take this one step at a time. 15q11-q13 duplication autism spectrum disorder refers to an issue with chromosome 15 and in particular with something called the PWS/AS critical region; that is a genetic area thought to be linked to the presentation of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) depending on whether inheritance is maternal or paternal. Autism has also been tied into the 15q11-q13 region as per studies like this one from Cook and colleagues**. There is quite a bit of other research on 15q11-q13 and autism in the scientific literature which can be browsed here.

POPs are basically those chemicals/compounds which stick around in the environment and seem not to be easily environmentally degradable. POPs include a range of compounds (see here) some (many?) of which also have the ability to bioaccumulate and potentially cause some quite serious effects on health as per what happened with Yushō disease. I don't want to get too heavily into the nitty-gritty of the health impacts of POPs simply because it is a very complicated area of environmental health sciences.

Certain POPs have been mentioned previously with autism / autistic behaviours in mind as per these archive posts on polybrominated diphenyl ethers (PBDEs) and autism and the flame-proofed mice with a Rett syndrome mutation study. This last study incidentally is also from Prof Janine LaSalle who also heads the current paper.

Mitchell et al report a few things in their study. I'm sorry that I can't post a link to the full-text paper, so you'll have to take my word for it:

• The lipid-rich brain tissue of one hundred and seven human postmortem brain samples were analysed for the presence of 8 polychlorinated biphenyl (PCB) and 7 PBDE congeners via GC-MS among other things. Samples were derived from deceased patients who were diagnosed with various neurodevelopmental disorders of 'known' origin (PWS, AS, Rett syndrome, 15q11-q13 duplication syndromes; n=32), idiopathic autism "of unknown etiology" (n=32) and asymptomatic controls (n=34). Age ranges were wide; between 4 - 61 years old at death across the groups.
• "Unexpectedly, PCB 95 was significantly (p<0.001) higher in the genetic neurodevelopmental group, but not idiopathic autism, as compared to neurotypical controls". Indeed out of 8 PCB congeners analysed, the genetic neurodevelopmental group showed the greatest mean concentration in  5 (although not significantly different levels).
• Furthermore, levels of PCB 95 seemed to be specifically tied to those diagnosed with a maternal15q11-q13 duplication (Dup15q) or deletion in Prader-Willi syndrome.
• Further analysis based on birth date pre- and post- 1976 (used because of the introduction of the 1976 Toxic Substances Control Act which is looking to be replaced by the Safe Chemicals Act of 2011) suggested that levels of PCB 95 were highest in the genetic neurodevelopmental group both pre- and post-1976. 
• A possible connection between PCB 95 and DNA methylation levels in Dup15q samples was undertaken by pyrosequencing for repetitive LINE-1 methylation levels ('similar' to this method). As would probably be expected, significant DNA hypomethylation was recorded compared with control samples (approximately 2% decrease in average methylation). That being said, year of birth was a confounder in that those controls born in the 1980s-1990s tended to show lower methylating functioning than those born in the 1960s-1970s. 
• PBDE levels showed little significant differences across the groups aside that is from one congener, PBDE 153, which showed a greater mean concentration in the control group compared to the other symptomatic groups (p<0.05).

I'm intrigued. To quote again from this study: "Our results demonstrated that 3/6 Prader-Willi syndrome and 5/6 Dup15q brain samples showed detectable levels of PCB 95 suggesting that this exposure should be investigated as a potential environmental contributor of the differing copy number variation rates in different regions".

Now I'm not saying that POPs 'cause' 15q11-q13 duplication autism spectrum disorder; the evidence just isn't there to suggest something so direct. As with every study which includes a postmortem element to it, there is always the sensitive issues of why the person died and whether comorbidity (epilepsy, learning disability?) might play an interfering role in any results obtained. It certainly is however an area that needs a lot more investigation.

I've often talked about mutations like SNPs and CNVs in relation to autism and a few other conditions (see here for example); the latest being that stark quote "no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level" from the paper by Richard Anney and colleagues (see post here). Where SNPs and/or CNVs do occur however, particularly when described as de novo as in the recent paper on paternal age and de novo mutations (see here), the question has to be why do such mutations occur outside of just a generic 'randomly based on age' argument? Without tempting too much criticism, I have to admit that 'random' just doesn't wash with me; there has to be a reason. One candidate outside of just maturation has to be environment.

A few final points to make and then I'm done. This is not the first time that PCB 95 has cropped up and interestingly has been previously tied into autism and calcium signalling as per this study by Wayman and colleagues*** (full-text). The issue of DNA hypomethylation and autism has also been covered on this blog previously so I'm not going to get too involved in that at this time.

And relax.

Despite the small participant numbers included in the study, I will say once again that I am intrigued by the results presented by Mitchell and colleagues and very much look forward to hearing more from this research group and others on our seemingly very delicate relationship with the modern environment around us.

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* Mitchell MM. et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental & Molecular Mutagenesis. August 2012.

** Cook EH Jr. et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics. 1997; 60: 928-934.

*** Wayman GA. et al. PCB-95 Modulates the Calcium-Dependent Signaling Pathway Responsible for Activity-Dependent Dendritic Growth. Environmental Health Perspectives. 2012; 120: 1003-1009.

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Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, & Lasalle JM (2012). Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environmental and molecular mutagenesis PMID: 22930557