"Minor physical anomalies" and autism: hypermobility very much included

'Minor physical anomalies' (MPAs) are defined as "subtle, abnormal morphological features, such as deviations in morphology of the head, eyes, ears, mouth, hands, and feet." I appreciate that such a term is probably not going to everyone's cup of tea, but given the embryological links between organs such as the brain and skin, it's assumed that "MPAs may mirror altered brain development."

That was the starting point for the study results published by Lynnea Myers and colleagues [1] looking for the presence of MPAs in a cohort of over 110 twins, around half of whom had received a concordant or discordant neurodevelopmental disorder diagnosis such as "intellectual disability (ID), communication disorders, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), specific learning disorders, and motor disorders." Alongside various behavioural and diagnostic assessments, researchers also used a special MPA checklist "containing a total of 179 anomalies for males (24 body regions) and 171 for females (23 body regions)" with their cohort. This checklist also included various other 'issues' that are "commonly assessed for in physical exams."

Various results were produced bearing in mind the quite complicated participant mix included for study (i.e. presence or not of a neurodevelopmental disorder, concordance among twins, zygosity, specific neurodevelopmental diagnosis, etc). Autism was the only neurodevelopmental diagnosis that was "significantly associated with the extent of MPAs." If twins were concordant for autism or autism spectrum disorder (ASD), researchers observed that they "had descriptively the highest median (Md) number of MPAs." Where twins were discordant - one had autism, the other not - researchers still observed MPAs, albeit to a slightly lesser degree (number). Further: "The most common MPAs in participants with ASD included overweight (39%), hypermobility (36%), pes planus (29%), straight eyebrows (29%), vision impairment (25%; 29% of these with corrective lenses), arachnodactyly/long toes (25%), long eyelashes (21%), and microtia (21%)."

Putting to one side the important findings that almost 40% of those with ASD were described as overweight (see here) or that vision issues were present in a quarter (see here), I was drawn to the suggestion that quite a percentage of those with autism (36%) were described as having hypermobility. Hypermobility, where joints are more flexible than usual, in the context of autism is something of an interest of mine (see here and see here). Not least because it is an area of the autism research landscape crying out for a lot more investigation, both as part of a wider 'psychiatric picture' (see here) and also in the 'ESSENCE' context that autism rarely exists in some sort of diagnostic vacuum (see here).

Minus any sweeping generalisations, there are a few potentially important implications either linked to or arising from hypermobility in the context of autism. Poor balance and/or coordination is one possible outcome from hypermobility that would perhaps tie into what has been discussed in the autism research literature for years and years now [2] (even Kanner mentioned it). The observation that functional gastrointestinal (GI) issues such as constipation and diarrhoea also seem to be over-represented in relation to hypermobility [3] also potentially accords with findings pertinent to quite a lot of autism (see here) (bearing in mind that I'm not saying that all bowel issues noted in autism are necessarily hypermobility-connected). If however one was to stretch things further, one might be looking at something like joint hypermobility in the context of connective tissue disorder and what that could mean for something like intestinal permeability issues associated with 'some' autism (see here). I know this is speculative, but at least it provides a research plan of action to include in future investigations in this area.

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[1] Myers L. et al. Minor physical anomalies in neurodevelopmental disorders: a twin study. Child and Adolescent Psychiatry and Mental Health. 2017; 11: 57.

[2] Cassidy S. et al. Dyspraxia and autistic traits in adults with and without autism spectrum conditions. Mol Autism. 2016 Nov 25;7:48.

[3] Fikree A. et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study. Neurogastroenterol Motil. 2015 Apr;27(4):569-79.

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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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"early medical events are associated with clinical ASD phenotypes"

The paper by Charlotte Willfors and colleagues [1] (open-access) provides some food for thought today and the observation that various individual and cumulative medical events - "early medical events likely to be caused by environmental factors" - may be important to at least some autism.

Researchers "scrutinized the early medical histories of a rare and informative sample of 13 MZ [monozygotic] twin pairs discordant for clinical ASD [autism spectrum disorder]" also including "13 MZ typically developing (TD) control pairs (n=52) matched for sex" as an 'exploratory step. Discordant for autism means that one twin had autism and the other did not.

This research first step looked at medical events (likely to be caused by environmental factors!) included things like delivery and neonatal variables (e.g. foetal distress, hypoxia), minor and frequent infections (e.g. ear infections), allergy and epilepsy to name a few. Data was acquired from a few sources including medical records and medical history "assessed from a parent reported questionnaire." They examined exposure to the medical events "in relation to either quantitative or qualitative discordance for ASD." Qualitative discordance referred to when "only one twin within a pair meeting the diagnostic criteria of ASD." A 'confirmatory' study was also carried out whereby a larger, independent cohort of 100 twin pairs "quantitatively discordant for autistic traits" were also quizzed and findings cross-validated.

Results: a few non-shared environmental (NSE) events seemed to be important based on their analysis. So: "Single early medical factors, likely to be caused by NSE, that discriminated between twins in qualitative ASD discordant pairs were dysregulation during the first year of life (comprising feeding and sleeping problems, excessive crying and worrying) and birth weight." Authors also reported that cumulatively, the appearance of early medical events were significantly different in MZ twins with autism compared with their non-ASD co-twin. It's worth mentioning that some of those 'dysregulation' events have been talked about in the earliest descriptions of autism (see here). Birth weight too has something of a long-standing connection to [some] autism (see here). When it came to analysis based on autistic traits (the confirmatory study) it seemed that "early dysregulation and the cumulative load of a variety of early adverse medical events" continued to be important variables (although birth weight linked to ASD traits lost its significance).

These are important findings. The focus on MZ twins (who share a common structural genetic blueprint) means that the genetics side of things is to a large extent 'controlled for' and the results are more likely to reflect some environmental or, more accurately, non-genetic influence. There is a caveat to this though, as per the authors recognition: "with the exception of putative post-twinning de novo mutations." I might also add that MZ twins are also not necessarily epigenetically the same too so gene expression can (and does) differ. What causes these epigenetic differences is still the source of some debate but I might chime in with one idea (see here) out of many possibilities.

"Our data indicate that taking into account the cumulative load of early medical factors might strengthen or discourage a suspicion of ASD, at least in a minority of cases." This is an interesting thought provided by the authors based on their findings. It ties in well with the idea that although behavioural presentation is core to autism presentation and diagnosis, behaviour might not be the only important feature present in relation to autism. I do have to express a degree of caution however with such an approach based on the idea that various types of regression have been noted in the peer-reviewed literature to accompany some autism (see here) and with it, the concept of 'acquired autism' should really be properly recognised (see here for example) in these days of the plural 'autisms'. Indeed, there's a research study idea for anyone out there: looking at MZ twins discordant for autism with onset of said autism tied into a regression of skills?

Scientific replication is the name of the [future] game in this area of study, drawing on larger cohorts and perhaps based in other geographical areas outside of Sweden. We also need to find out what mechanisms might be potentially associating something like 'early dysregulation' with the onset of autism, taking into account how factors such as early feeding practices/issues for example, might provide at least one avenue for future study (see here).

To close, in light of some recent media headlines about the 'myth' that autism rates are on the up (and quite significantly so over past two decades), I offer some past posts suggesting that the word 'myth' should be reserved for other [non-peer-reviewed] matters (see here and see here and see here) and not this particular branch of epidemiological science. As to what may be 'causing' the upswing in numbers of diagnosed cases, well, it's likely to be very, very, very complicated (and without any need for sweeping generalisations please)...

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[1] Willfors C. et al. Medical history of discordant twins and environmental etiologies of autism. Transl Psychiatry. 2017 Jan 31;7(1):e1014.

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Willfors C, Carlsson T, Anderlid BM, Nordgren A, Kostrzewa E, Berggren S, Ronald A, Kuja-Halkola R, Tammimies K, & Bölte S (2017). Medical history of discordant twins and environmental etiologies of autism. Translational psychiatry, 7 (1) PMID: 28140403

Yet more on potential biomarkers and chronic fatigue syndrome

'Thick and fast' is probably the best way that I can describe the flurry of peer-reviewed scientific papers recently appearing (see here and see here for examples) talking about how chronic fatigue syndrome (CFS) (also linked to the diagnosis of myalgic encephalomyelitis, ME) might have some important biological processes attached to it.

Now we can add the findings reported by Federica Ciregia and colleagues [1] (open-access) to the list and their observations that "the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS."

The Ciregia paper is open-access but well-worth a few inches of discussion on this blog. Not least because (a) the word 'mitochondria' is part and parcel of the their findings in line with other research in this area, (b) one of the gold standards of analytical chemistry - liquid chromatography mass spectrometry -  was used, and (c) some of the findings are based on a study of twins: "a patient suffering from CFS in comparison with his healthy monozygotic twin." This mirrors other similar published work from this authorship group [2].

So, using a discovery/training and validation approach similar to other biomarker studies in other areas, researchers initially set out to "study the mitochondria extracted from platelets of the twins" using "nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS)." They were looking for evidence of different compounds being presented/expressed in those twins diagnosed with CFS compared with their non-affected twin and eventually came up with 41 proteins - "34 were upregulated in CFS and 7 were downregulated" (see here for the list of compounds).

Using a process called Ingenuity Pathway Analysis (IPA) "to retrieve the known functions of each protein" authors were able to visualise where each compound 'fitted' in terms of specific biological functions. The top three included: "metabolism of isocitric acid..., metabolism of NADH... and metabolism of nucleic-acid component or derivative." Certainly NADH has some 'history' when it comes to CFS/ME (see here).

Then came the validation side of the study where "the most promising biomarkers were validated by western blot [WB] analysis in a big cohort of patients, using whole saliva (WS)." Here some 45 patients diagnosed with CFS ("based on the classification criteria of Fukuda et al") were recruited alongside 45 not-CFS controls and spit samples from all were analysed for "aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM)." Two proteins, ACON and ATPB. were replicated or at least "consistent with the results from nano-LC-MS."

Finally, researchers looked at whether presented clinical features as described in various questionnaires delivered to participants might play a role in the presentation of their biological results. They did see something (see here) - "For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin" - but I would be minded to suggest that quite a bit more work is needed before anyone reads too much into this as the results stand.

So, there you have it. A little bit more evidence to suggest that science is edging a little closer to potentially identifying some of the biology behind (or least associated with) at least some CFS (and ME). A little bit more peer-reviewed evidence moving the discussions away from 'psychosomatic' [3] to something a little more testable/analysable with CFS/ME in mind (I'll be coming to the paper by Geraghty & Esmail soon enough on this blog by the way). Independent replication is the next step, onwards to potentially "developing tailored treatments." That bearing in mind, we already have some emerging data in this area too (see here) (with no medical advice given or intended).

And just in case you want yet more potential biomarker research for CFS, here's another paper that has just been published [4]. Thick and fast people, thick and fast.

So, there is a new trailer for Rogue One (A Star Wars story)...

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[1] Ciregia F. et al. Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Transl Psychiatry. 2016 Sep 27;6(9):e904.

[2] Ciregia F. et al. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2;11:243.

[3] Geraghty KJ. & Esmail A. Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? Br J General Practitioners. 2016. Aug 1.

[4] Yamano E. et al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Scientific Reports. 2016; 6: 34990.

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Ciregia F, Kollipara L, Giusti L, Zahedi RP, Giacomelli C, Mazzoni MR, Giannaccini G, Scarpellini P, Urbani A, Sickmann A, Lucacchini A, & Bazzichi L (2016). Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Translational psychiatry, 6 (9) PMID: 27676445

Assisted Reproductive Technology conception and autism

I noticed recently that the paper by Christine Fountain and colleagues [1] reporting that "incidence of diagnosed autism was twice as high for ART [assisted reproductive technology] as non-ART births" has been making some media headlines.

Based on an analysis of an impressive participant number "using linked records from the California Birth Master Files for 1997 through 2007, the California Department of Developmental Services autism caseload for 1997 through 2011, and the Centers for Disease Control and Prevention's National ART Surveillance System for live births in 1997 through 2007" authors looked at nearly 6 million births in California, USA. Including nearly 49,000 "ART-originated infants" and 33,000 "cases of autism diagnosed by the Department of Developmental Services", they set about looking at whether there was any difference between "births originated using ART with births originated without ART for incidence of autism."

They concluded that there was perhaps more to see when it came to ART births and autism albeit not necessarily a clear-cut relationship. Multiple births and "adverse prenatal and perinatal outcomes" seemed to play quite an important role in the 'association' reported, leading to quotes like this from others: "The results indicate that reducing multiple births during ART may be beneficial for decreasing the risk of autism."

This is not the first time that ART and some of the specific techniques linked to ART such as IVF (in vitro fertilisation) have been talked about with autism in mind. I have discussed the topic previously on this blog (see here) based on the findings reported by Venla Lehti and colleagues [2] for example. In that case, as in other instances [3], the results were less than impressive on any general association. These independent analyses did not rule out specific factors perhaps requiring further investigation, but overall the effect of ART on general autism risk was not particularly great.

The take-home message is that whilst ART might impact on autism risk, the techniques themselves included under the ART banner are probably not the primary source of any risk. Rather, as we've seen on quite a few other occasions, issues around gestation and birth (see here) might be the important variables which itself asks some interesting questions about autism research areas such as the use of twins (see here) among other things...

Music: Rihanna et al - Umbrella.

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[1] Fountain C. et al. Association Between Assisted Reproductive Technology Conception and Autism in California, 1997-2007. Am J Public Health. 2015 Mar 19:e1-e9.

[2] Lehti V. et al. Autism spectrum disorders in IVF children: a national case-control study in Finland. Hum Reprod. 2013 Mar;28(3):812-8.

[3] Sandin S. et al. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013 Jul 3;310(1):75-84.

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Fountain C, Zhang Y, Kissin DM, Schieve LA, Jamieson DJ, Rice C, & Bearman P (2015). Association Between Assisted Reproductive Technology Conception and Autism in California, 1997-2007. American journal of public health PMID: 25790396

Autism, heritability and 'proof of principle' genomic biomarkers

JAMA Psychiatry published a number of interesting articles recently, some of which have grabbed media headlines. "Autism is largely down to genes, twin study suggests" went the BBC headline covering the paper by Emma Colvert and colleagues [1] who, based on an analysis of twin pairs as part of TEDS (Twins Early Development Study), concluded that: "The liability to ASD [autism spectrum disorder] and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects." 

The paper from Tiziano Pramparo and colleagues [2] has so far garnered rather less media attention with their "proof-of-principle study" suggesting that "genomic biomarkers with very good sensitivity and specificity for boys with ASD in general pediatric settings can be identified." Said results were based on examination of "leukocyte RNA expression levels" and found some interesting differences between children diagnosed with autism vs. asymptomatic controls including functions relevant to the immune system and inflammatory processes among other things. Go figure.

The Colvert paper covers one of the more heated debates when it comes to autism: the relative contributions of genetics vs. environment to autism. I've covered this issues quite a bit on this blog, perhaps most recently when discussing the paper from Sven Sandin and colleagues [3] and their results leading to press releases stating that: "Environment as important as genes in autism, study finds." The Colvert results seem to have something slightly different to say, following a well trodden path in autism research of results and counter-results swinging pendulum style (see here).

I don't want to trawl over every detail of the Colvert study but it strikes me that there are a few important things to say about the findings within the context of both genes vs. environment and also the growing move towards the plural 'autisms'. First, is their reliance on looking at twin pairs and in particular, some who were monozygotic (MZ) twins and others who were dizygotic (DZ) combined with an analysis of assessed autistic traits in said twins. In effect, authors were comparing twin pairs - MZ vs. DZ - for how well they matched in autism symptoms terms as a function of their degree of genetic similarity. They didn't actually look at the genes potentially involved in autism in this study, which as we have found out from the paper by Ryan Yuen and colleagues [4], are likely to be pretty complex and containing "substantial genetic heterogeneity" even within sibling pairs (see here for my take on this). And yes, I know 'siblings' are not necessarily the same as 'twins'...

There are also some implicit statements in the study of twins. We assume that they are genetically identical (at least MZ twins). Unfortunately, more and more science is realising that sharing the same genes is not necessarily the same as sharing the same gene functions. One word: epigenetics, and as we've seen even with autism in mind, how issues such as DNA methylation mean twins (identical twins) are not necessarily as identical as you might imagine (see here) and how this might explain at least some of the missing heritability noted in such studies. The value-added bit to the study by Chloe Wong and colleagues [5] looking at the methylome with autism in mind was that they too relied on data from TEDS.

"The novel aspect of this study was the inclusion of twins regardless of whether they had a clinical diagnosis. This enabled us to get a more accurate picture of how influential a child’s environmental experiences and their genetic makeup is on ASD, as well as on subtler expressions of autistic skills and behaviours." A quote from one of the study authors also gives us something to ponder. I assume the 'subtler expressions' means the broader autism phenotype (BAP) and the idea that crossing the diagnostic threshold of autism (or ASD) means crossing a blurred barrier where the traits of autism are also present in milder, less pathological forms not necessarily meeting the diagnostic criteria that we've assigned for the condition. Whilst this is a strength of the Colvert paper over other research in this area, it does rather mean that the spotlight is on the 'trait phenotype' of autism. And 'fractionable' autistic traits have been a focus of other research by some of the authors [6] on the Colvert paper.

I'd also like to think that although the Colvert results are important from the point of view that there are potentially shared genes (or even shared epigenomic issues) at work when it comes to autism / autistic traits, this does not mean that such genes are on their own 'causative' of autism. "Some parents are concerned whether things like high pollution might be causing autism” is another quote from another of the study authors who seems to be downplaying the possibility that such environmental factors might play some hand in some autism. I'm similarly guarded about the idea that something like air pollution might 'correlate' with some autism but as we've discovered over recent years, one doesn't talk about environment without also mentioning the idea of genetic 'fragility' to certain environmental issues (see here) based on the preliminary findings from Heather Volk and colleagues [7] for example. That also genes which might predispose to autism may also predispose to other conditions/states as per the Pramparo paper talking about immune function and inflammatory processes is also worth reiterating.

I guess what I'm trying to say is that of course genes are going to be involved in autism. Even those cases of autism where onset is linked to something like infection (see here and see here) or has a regressive element to it (see here), there has to be some genetic involvement. Genes however, don't typically act in isolation from either maturation or the environment they find themselves in. They're dynamic, switching on and off in various tissues in response to all-manner of different variables. Structural genetics, that is looking for the presence of mutations or different variants, is still important to autism research (as per the BCKDK gene work) of that there is no doubt, although even there the processes dictating mutation are likely to be complex. But within the wide - very wide - spectrum included under the diagnosis of autism, I'd be inclined to suggest that science shouldn't yet be ready to give up the idea that environment (however this is interpreted) might yet hold some important clues about some autism...

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[1] Colvert E. et al. Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample. JAMA Psychiatry. 2015 Mar 4.

[2] Pramparo T. et al. Prediction of Autism by Translation and Immune/Inflammation Coexpressed Genes in Toddlers From Pediatric Community Practices. JAMA Psychiatry. 2015 Mar 4.

[3] Sandin S. et al. The familial risk of autism. JAMA. 2014 May 7;311(17):1770-7.

[4] Yuen RK. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med. 2015 Feb;21(2):185-91.

[5] Wong CC. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry. 2014 Apr;19(4):495-503.

[6] Brunsdon VE. & Happé F. Exploring the 'fractionation' of autism at the cognitive level. Autism. 2014 Jan;18(1):17-30.

[7] Volk HE. et al. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014 Jan;25(1):44-7.

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Colvert, E., Tick, B., McEwen, F., Stewart, C., Curran, S., Woodhouse, E., Gillan, N., Hallett, V., Lietz, S., Garnett, T., Ronald, A., Plomin, R., Rijsdijk, F., Happé, F., & Bolton, P. (2015). Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.3028




Pramparo, T., Pierce, K., Lombardo, M., Carter Barnes, C., Marinero, S., Ahrens-Barbeau, C., Murray, S., Lopez, L., Xu, R., & Courchesne, E. (2015). Prediction of Autism by Translation and Immune/Inflammation Coexpressed Genes in Toddlers From Pediatric Community Practices JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2014.3008

Heightened anxiety in children with autism

Given that a certain portly chap with a white beard (yes, one of those fat yet fit types) is heading the way of many a household over the coming hours, I'm going to be quite brief in this post about the paper by Victoria Hallett and colleagues* who concluded that their "findings support previous reports of heightened anxiety in children with ASDs [autism spectrum disorders]". The realisation that Christmas can itself be a significant source of anxiety to many people as per the BBC article (here) is perhaps also worth directing your attention to, given the potential for overlap when discussing autism.

By Emile not Santa [Claus] @ Wikipedia 

I've talked (and talked) about how various forms of anxiety do seem to be over-represented when it comes to autism (see here for the mega-post) and the various ways and means that science has so far offered when it comes to helping to manage or relieve such issues, acknowledging that we still have some distance to go on this topic.

The Hallett paper in respect of finding 'parent-reported' anxiety to be present in children with autism is no new thing. That being said, their analysis based on data from TEDS (Twins Early Development Study) adds a new twist to the research in this area, as does their suggestion that "Unaffected co-twins of children with ASDs also showed increased anxiety, generating questions about the potential etiological overlap between ASDs and anxiety". Yes it certainly does generate questions, and in particular, whether the broader autism phenotype (BAP) might have another potential diagnostic string to add to its bow.

I note that at least some of this authorship group have previously talked about autism, twins and issues like anxiety (as part of the so-called internalising traits) as per papers like this one** and this one***. I was drawn to a particular quote in one of those papers: "these traits may serve to exacerbate each other over time" suggestive that intervention-wise at least, treating something like anxiety might have some interesting knock-on effects on the presentation of core autism traits and vice-versa. Another discussion for another time methinks, perhaps alongside the recent paper by Boulter and colleagues**** on intolerance of uncertainty in relation to anxiety present in cases of autism?

Anyhow, without further ado, I wish you all Happy Christmas or Seasons Greetings if you prefer. Stay tuned for the mega-roundup post of autism research that has appeared on this blog during 2013 coming up in the next few days. I leave you with some sound advice when it comes to cooking that over-sized turkey that you've probably bought to avoid any unfortunate incidents or undesirable trips to the smallest room in the house. Oh, and some research news that will hopefully raise a smile to any Hobbit fan...

And just before I go, yet again Shane and Kirsty perform for you the best Christmas song ever...

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* Hallett V. et al. Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls. J Child Psychol Psychiatry. 2013 Nov;54(11):1176-85.

** Hallett V. et al. Association of autistic-like and internalizing traits during childhood: a longitudinal twin study. Am J Psychiatry. 2010 Jul;167(7):809-17. 

*** Hallett V. et al. Investigating the association between autistic-like and internalizing traits in a community-based twin sample. J Am Acad Child Adolesc Psychiatry. 2009 Jun;48(6):618-27.

**** Boulter C. et al. Intolerance of Uncertainty as a Framework for Understanding Anxiety in Children and Adolescents with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Nov 24. 

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Hallett V, Ronald A, Colvert E, Ames C, Woodhouse E, Lietz S, Garnett T, Gillan N, Rijsdijk F, Scahill L, Bolton P, & Happé F. (2013). Exploring anxiety symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins and controls J Child Psychol Psychiatry, 54 (11), 1176-1185 DOI: 10.1111/jcpp.12068

Autism and the methylome

Q: When is an identical twin not an identical twin? A: Pretty much all the time (at least according to some people) as our increasing understanding of the complexity of genetics stretches and modifies long-held beliefs about the building blocks of life and their role in our health and wellbeing.

DNA methylation differences? @ Wikipedia  

Today I'm talking about identical (monozygotic) twins - siblings derived from one fertilised egg - and how the science of epigenetics might have some interesting implications for autism research as per the study by Chloe Wong and colleagues* (open-access). I should perhaps also direct you to some other interesting research recently discussed in this area too (see here) which might be relevant.

Regular readers will probably already know about my amateur interest in epigenetics (see here and here) and how the area of the epigenome - those chemical marks which have the ability to influence the expression of the genome - has started to yield some potentially important observations. At times I'll admit to being slightly too over-excited at the possibilities of epigenetics. Subsequently brought back down to earth by more sobering accounts (see here**) but not yet ready to poo-poo the whole science just yet***.

I don't want to rehash the whole epigenetic story in this one post, so instead am going to concentrate on the particular area covered by Wong et al and their analysis of the methylome (yes, another -ome for you) which is concerned with the addition of methyl groups to various regions of the genome and how that subsequently alters the expression of genes. DNA methylation has been a sort of peripheral topic in relation to cases of autism for quite some time now; brought to the forefront by all that folic acid (see here) and MTHFR research (see here) and the availability of those lovely methyl groups. Suffice to say that we are still very much at the beginning when it comes to looking at the relationship between all these elements and very complicated conditions like autism.

Anyhow, after that very long introduction (I am only an amateur science blogger after all), a few details from the Wong paper might be in order, bearing in mind it is open-access:

• Part of the UK TEDS initiative and partly sponsored by Autism Speaks who were involved in that recent environmental epigenetics symposium (see here), researchers looked at 50 monozygotic (MZ) twin pairs. It wasn't just a case of 25 twin pairs where one twin was diagnosed with an autism spectrum disorder (ASD) compared with 25 twin pairs where both were concordant for ASD. No, instead the authors looked at a variety of phenotypic combinations based on concordance/discordance for ASD and various core traits based on the Childhood Autism Symptom Test (CAST) schedule. Supplementary table 1 shows the combinations (see here).
• A genome-wide analysis of DNA methylation was undertaken on blood samples provided by participants. I can't pretend to intimately know all the techniques that were employed so won't profess to do so. What I can glean from the paper is that both DNA methylation differences between MZ twin pairs discordant for ASD and analyses between groups scoring high and low on the various core symptom areas were completed with "the aim of identifying real, biologically relevant within-twin and between group DNA methylation differences".
• Results: "ASD is not associated with systemic differences in global DNA methylation". In other words, within the twins, there is quite a high degree of similarity when it comes to patterns of DNA methylation. This might tie in with other work looking at methylation in cases of autism and other family members (see here). 
• When looking at DNA methylation patterns between twin pairs discordant for ASD, specific sites of the genome however seemed to show some variability as a function of ASD diagnosis or not. The authors list the top 50 "differentially methylated CpG sites" (see here) showing gene and position, with a combination of hyper- and hypo-methylated regions identified. Top of the methylation differences pops was the NFYC promoter which was "consistently hypermethylated in affected individuals" (see here for some additional papers on this gene). Hypermethylation by the way, generally means gene silencing as per its function when it comes to transposons (think HERVs). 
• Various other data are presented based on either syndrome or trait specific differences across the twins. I'm not going to go through all of these because, well because that's called plagiarism. I will draw your attention to one particular finding which might be important as they identified "one MZ twin pair, concordant for a very severe autistic phenotype, that appear to represent epigenetic outliers at multiple CpG sites across the genome". I'm immediately drawn back to my autism or autisms post and that all-important phenotypic variability as potentially being relevant here too. That and the tie-up with more structural changes to the genome as per the mention of CNVs and hotspots.

I know I've gone on a bit in the post but this is potentially a very important paper. Not only does it put the epigenome, or at least one part of the epigenome, firmly on the autism research map, but it offers something of a partial explanation for [some of] that 'missing heritability' which was talked about not so many years ago (see here).

The fact also that methylation patterns might be variable both intra-twins and intra-ASD is also important; suggesting that as with more traditional genomic findings in relation to autism, there isn't going to be just one epigenomic factor affecting risk or presentation, but rather a plethora of sites which are hyper- or hypo-methylated, potentially also linked to (affecting?) more structural changes to the genome in cases of ASD.

Don't get me wrong, the same questions remain as are seen in other areas of biological functioning with autism in mind: the heterogeneity, the reliance on diagnosis by observation and note-taking, the (elevated) risk of comorbidities, etc. All of which cloud the waters of association. Distinct however from the question of whether there is anything that can be done when structural changes to the genome are observed (outside of gene therapy for example), when talking about methylation, one speculates that this might be something that lends itself to pharmacotherapy as per the already use of DNA methyltransferase inhibitors for example. Yes, going back to that folic acid-autism link work, the possibility also that environment might help shape gene function and some new light on other external factors (noting that I am not advocating anything at the current time).

So endth the lesson for today.

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* Wong CC. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Molecular Psychiatry. April 2013.

** Ptashne M. Epigenetics: core misconcept. PNAS. April 2013.

*** Fraga MF. et al. Epigenetic differences arise during the lifetime of monozygotic twins. PNAS. 2005; 102: 10604-10609.

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Wong, C., Meaburn, E., Ronald, A., Price, T., Jeffries, A., Schalkwyk, L., Plomin, R., & Mill, J. (2013). Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits Molecular Psychiatry DOI: 10.1038/mp.2013.41

On the broader autism phenotype

I think most people would be satisfied with the description of autism as a spectral condition epitomised by the phrase 'if you've met one person with autism, you've met one person with autism'. The term 'autism spectrum' denotes the heterogeneity apparent and that the presentation of core symptoms varies intra-diagnosis according to symptom domain as well as inter-person across different individuals. This is independent of the fluctuations in presentation across different situations and not including variables like maturation, co-morbidity and any effect from intervention.

A spectrum also implies other things including degrees of severity between two poles; ranging from very severe 'disability' at one end to 'difference' at the other end (as per this description from Lorna Wing) depending on your definition and how you grade severity. In between you have a mix of ability and disability. I should point out that by using the term 'difference' I am not in anyway suggesting that those at that end of the spectrum are in any way less deserving of the appropriate support and services. High functioning - however you describe this - does not always mean 'can function'.

At the less severe end of the spectrum, a cut-off point is generally accepted to exist in some shape or form; in diagnostic terms denoting presentation which somehow surpasses a clinical threshold and in cold hard psychiatric terms implies psychopathology. The rights and wrongs of where the threshold has been currently set still continues to create lively debate. The presence of that diagnostic threshold however does not necessarily denote the 'end of the autism spectrum' from a real-world behavioural perspective. It implies the end of the diagnostic spectrum but not that the subtle presentation of certain autistic traits cannot be present beyond the clinical spectrum. Enter the broader autism phenotype (BAP) as evidence of this extra-diagnostic spectrum of presentation.

I first heard about the BAP quite early on in my research career. Prof. Ann Le Couteur, one of the early proponents of the BAP discussed some of the ins and outs of the concept and in particular based on studies of siblings of children with autism, how issues like speech and language problems and social interactive issues were picked up from time to time which did not quite fulfil autism diagnostic criteria either in measure or severity. I also remember quite a few people talking about the overlap with certain personality traits such as introversion and more recently some work looking at autistic traits in conditions such as feeding disorders.

Much of the early work on BAP was tied into the genetic basis of autism based on twin studies, the strength of which has recently come under scrutiny. With this in mind, a recent paper by Davidson and colleagues* caught my eye with their suggestion ".. that BAP traits occur at low rates in simplex families". The results reported in this recent paper were based on an examination of the Simons Simplex Collection which as the name suggests contains details of samples from around 2700 families with one child diagnosed with an autism spectrum condition. Davidson et al looked at over 1500 of these families with the purpose of trying to further elucidate what the BAP is and how it could be appropriately tested for and measured.

I'm intrigued about the potential for differences in BAP traits according to whether a family has one child with autism or more than one. The obvious issue with this study is its exclusive analysis of simplex families, so nothing to compare against in terms of multiplex families outside of external datasets. That and the reliance on a snapshot of where a family is in terms of autism not necessarily ruling out any elevated risk of autism recurrence in simplex families should for example they have other children. This last point is perhaps a fundamental flaw in any simplex analysis.

Putting these issues aside, the first thing that comes to mind is whether the weighting of genetics vs. environment might be different in simplex families where BAP traits are infrequent. In other words, is there a suggestion that environmental factors might trump genetic factors in such cases compared to other families where BAP traits are more frequent in other family members? It is perhaps not as easy to say one is genetic and the other is environment because such simple arguments have not been borne out by the research data and most (if not all) conditions are likely to be the result of an interplay between nature and nurture. Think epigenetics for example.

If the data from Davidson is accurate however, this might provide a good opportunity to look at factors such as regression, comorbidity and early adverse events to determine any difference in individuals with autism among high and low BAP trait families. At the very least if offers another potential phenotypic distinction which could be added to those already being looked at.

* Davidson J. et al. Expression of the Broad Autism Phenotype in Simplex Autism Families from the Simons Simplex Collection. JADD. March 2012.
DOI: 10.1007/s10803-012-1492-1

Twins and autism: a response

A very short post this one, I promise.

Following the revelations yesterday that the genetic contribution to autism 'might' have been inflated, there has been quite a lot of scientific and media interest in this whole debate. I say media interest, but here in the UK we have heard diddly squat so far about the revelations that identical twins appear to show a not so high rate of autism than fraternal twins. I don't know why.

Anyway, I would like to draw attention to this opinion piece published in the Archives of General Psychiatry (online) by Dr Peter Szatmari of McMaster University and his take on the implications of the Hallmayer paper. Szatmari is no stranger to autism research having published extensively with papers such as this one and this one.

He is fairly candid in his opinions on the 'game changer' that was the Hallmayer paper and the implications for the early concordance studies such as that from Folstein and Rutter in 1977, asking "where did the heritability go?". Whilst I wouldn't like to give a definitive answer to this complicated question, I would perhaps suggest that we should start by looking at the participant numbers included in the Folstein paper - 21 twin pairs. That's all. Forty-two participants. That is pretty much what the whole 'genetics are king' argument was originally based on. I know that this study has been replicated in other participant groups but be under no disillusion that the 1977 paper cast the die.

Many, many people have been talking about the variable relationship between genes and environment in autism down the years. I'd like to think that once the dust has settled and further corroborative work completed (part of which should be appearing in the journal Pediatrics soon), autism research can finally move out of its 'obsession' with purely genetic models of autism and start moving itself into that brave new world in which genes work in unison with environment. At least so no more parents enter a Doctors office to be told blanket that 'autism is genetic' and nothing else.

Genes overestimated, environment underestimated in autism?

Only a short post this one in response to an article which has just appeared in the Archives of General Psychiatry titled: Genetic heritability and shared environmental factors among twin pairs with autism. A copy of the full-text paper can be found here.

For many years, genes have perhaps received the lion's share of attention when it comes to autism and autism research. Studies conducted in the late to mid 1990's and early noughties estimated a significant genetic loading for autism based on studies of the rates of autism in monozygotic and dizygotic twin pairs; that is twins derived from one egg and those derived from separate eggs. A few choice papers detailing such observations can be found here and here.

Whilst genes are important for autism (and nearly every other condition), there has been a bit of a sea-change in recent years away from notions of an 'autism gene' or genes to something a little more complex with regards to genes and environment. If you don't believe me, have a look at my various posts on CNVs and mutations studied with autism in mind.

This recent paper from Hallmayer and colleagues, corroborates the gene-environment interaction and indeed, perhaps swings the pendulum from genes to more of an environmental effect in terms of risk of developing autism. The collaborative study is a detailed one based in our old autism research favourite place California, where data from a very well-defined autism group, autism and broader autism using ADI-R and ADOS, were examined based on their monozygotic or dizygotic membership in order to ascertain whether autism rates were higher in identical twins than fraternal twins.

The study and findings: of the 202 twin pairs looked at (N=404), 242 twins reached the criteria for autism spectrum disorder (60%), of whom 171 twins met the stricter criteria for autism. Based on these data, 192 twin pairs were submitted for genetic analysis to ascertain zygosity, that is whether they were identical or fraternal twins based on various markers. Fifty-four pairs were found to be monozygotic (28%) and 138 were dizygotic (72%). There are other findings based on the breakdown of specific diagnosis and gender, but I perhaps need a little longer to go into those.

What this means is that if autism was a strongly genetic condition, one would expect that there would be a lot more twins with autism derived from the same egg, the same genetic material, than those derived from separate eggs. The fact that those from separate eggs showed a high-ish rate of autism implies that whilst genes might be important, there is perhaps also a significant contribution from some environmental factor/s in connection to a diagnosis of autism or autism spectrum disorder.

The authors do caution about the findings and issues such as their applicability to all diagnoses of autism across the various geographies and ethnicities. I have posted entries about some of these potential environmental factors previously (here and here for example) but as yet no-one has been able to specifically tie down what they might be and the specific temporal window of exposure. I do wonder also if there might be some influence of time in terms of the results found; is the autism of today, the same as the autism of yester-year?

Replication is the next stage of the process, replication in the same geographical area (or thereabouts) and replication overseas, like here in Northern Europe where many of the original genetic studies on autism were carried out. One would perhaps also like to see a little more information about whether the 'type' of autism might also show any effect and also covering the issue of the broader autism phenotype.

For now though, the sea-change continues as environment steps up to share centre-stage alongside genes in the very complicated world of autism research. The question is: will as much money be directed to the study of environmental factors and autism as has been spent on looking at genes?