Thursday, 19 October 2017

Weighing up genetics and environment in autism - reanalysed

Consider this post a sort of add-on to a previous entry (see here) published on this blog talking about the relative contributions of genetics and environment when it comes to autism. On that previous blogging occasion, the findings reported by Sven Sandin and colleagues [1] were the source material and the observation: "Heritability of ASD [autism spectrum disorder] and autistic disorder were estimated to be approximately 50%." The press release accompanying those results was titled: "Environment as important as genes in autism, study finds."

Now the same data has been though a bit of a re-analysis [2] and a slightly different conclusion and media headline - "Autism is mostly genetic, suggests study" - has been created. The reason for the quite different conclusions reached: "Instead of looking at just one time point when both members of a sibling pair had been diagnosed, they incorporated the fact that not all siblings would be diagnosed at the same time. They may start as being undiagnosed, then one would get diagnosed and, later, another might be determined to have autism" according to another media take on the findings (see here). I can't argue with the logic.

The data - 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs - were now analysed in the context that diagnoses of autism/ASD among siblings are, for many reasons, not always uniform in timing. The influence of genetics or more specifically, heritability was subsequently boosted up to 83% (previously suggested to be 50%) and with it, 'nonshared environmental influence' relegated to an estimates 17%.

I've perhaps been a little unfair by using the word 'relegated' in the context of non shared environmental influence in relation to autism. There are plenty of examples out there whereby such influences might impact on autism risk: prenatal valproate exposure, congenital rubella syndrome, various types of encephalitis being linked to autistic symptoms onset (see here and see here for examples), etc and these are not to be downplayed. Environmental factors can be pretty important.

But it's critical to also mention that genetics do seem to play quite a significant role in many instances of autism too. Yes, the idea of an 'autism gene' is already a distant memory replaced by something altogether a lot more complicated, but when taking into account notions such as the broader autism phenotype (BAP) for example, one cannot discount that particularly in multiplex families, heritability is probably [mostly] driven by genetics and science still needs to continue looking at the specific hows-and-whys (see here for one example). I might add that looking at gene expression over just structural genetics is probably going to be useful in these days of epigenetics and the like.

And whilst the research of Sven Sandin is being discussed today, another recent paper where the name has appeared [3] has suggested that "little or no maternal genetics contribution" is the order of things when it comes to heritability and autism...


[1] Sandin S. et al. The Familial Risk of Autism. JAMA 2014; 311: 1770-1777.

[2] Sandin S. et al. The Heritability of Autism Spectrum Disorder. JAMA. 2017; 318(12): 1182-1184.

[3] Yip BHK. et al. Heritable variation, with little or no maternal genetics contribution, accounts for recurrence risk to autism spectrum disorder in Sweden. Biological Psychiatry. 2017. Sept 21.


Wednesday, 18 October 2017

Tobacco smoking and psychiatric illness

"The prevalence of smoking has remained alarmingly high among individuals with schizophrenia and bipolar disorder, and the disparity with those without psychiatric disorders and with the general population is increasing."

So said the findings reported by Faith Dickerson and colleagues [1] who surveyed nearly 2000 people "about their cigarette smoking at enrollment into a research study for which they were selected without regard to their smoking status." Their findings make for important reading in the context that tobacco smoking is not exactly a healthy activity (see here) and could potentially contribute to some of the health inequalities already recognised when it comes to serious mental illness (SMI) (see here).

The sorts of figures of smoking prevalence observed by Dickerson et al are not to be ignored: "62% of individuals with schizophrenia, 37% with bipolar disorder, and 17% of participants without a psychiatric disorder (control group) reported that they were current smokers." This set in the context of falls in the rates of smoking in the general population. It's also worthwhile noting that being a 'current smoker' with reference to a diagnosis of schizophrenia or bipolar disorder typically meant smoking "more cigarettes per day" than the control cohort.

There are other implications from this work. Without generalising (or stigmatising) if one draws on other work talking about a possible connection between prenatal nicotine exposure and offspring [heightened] risk of schizophrenia for example (see here), a complex pattern of *association* seems to emerge. No, I'm not saying that every woman with schizophrenia who is pregnant will smoke through their pregnancy (despite evidence of some increased risk [2]) but greater focus and education on the need to restrict tobacco smoking during that critical period is perhaps warranted. Such discussions may also have implications for the whole nature-nurture debate with regards to such psychiatric diagnoses too.

Although there are many (many!) good reasons for encouraging those with a SMI to quit smoking, I do feel it is important also to understand why so many are smokers. The findings reported by Li and colleagues [3] offer something of a perspective on this issue where for example: "Smokers had a higher mental QOL [quality of life] than non-smokers... in MDD [major depressive disorder]." Similarly, Mallet and colleagues [4] discussed results that suggested that "some therapeutics may improve daily smoking behavior in smokers" in the context of schizophrenia (as others seemed to be associated with 'not improving' smoking behaviours). In short, the roads that lead to, and perpetuate tobacco smoking in the context of SMI are likely as complex as the ones needed to lead people away from such habits...

And aside from the health reasons to quit smoking particularly among those diagnosed with a SMI, the grand review, meta-analysis and meta-regression paper by Cassidy and colleagues [5] lists tobacco smoking as one potentially important (and modifiable) correlate when it comes to risk factors for suicidality in schizophrenia...


[1] Dickerson F. et al. Cigarette Smoking by Patients With Serious Mental Illness, 1999-2016: An Increasing Disparity. Psychiatr Serv. 2017 Sep 15:appips201700118.

[2] Nilsson E. et al. Women with schizophrenia: pregnancy outcome and infant death among their offspring. Schizophr Res. 2002 Dec 1;58(2-3):221-9.

[3] Li XH. et al. Prevalence of smoking in patients with bipolar disorder, major depressive disorder and schizophrenia and their relationships with quality of life. Sci Rep. 2017 Aug 16;7(1):8430.

[4] Mallet J. et al. Cigarette smoking and schizophrenia: a specific clinical and therapeutic profile? Results from the FACE-Schizophrenia cohort. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):332-339.

[5] Cassidy RM. et al. Risk Factors for Suicidality in Patients With Schizophrenia: A Systematic Review, Meta-analysis, and Meta-regression of 96 Studies. Schizophr Bull. 2017 Sep 23.


Tuesday, 17 October 2017

"What are the sex-specific recurrence rates of autism spectrum disorder among siblings?"

The paper by Nathan Palmer and colleagues [1] attempted to shed some light on the question posed in the title of this post: "What are the sex-specific recurrence rates of autism spectrum disorder among siblings?" The topic of sibling recurrence rates with regards to autism has been discussed for quite a few years (see here for example).

Already covered by Spectrum (see here), the Palmer data was derived from the records of a US health insurance organisation covering the period between 2008 and 2016 and some 3 million+ children. Researchers specifically looked at those in receipt of an autism diagnosis and onward to "estimate high-confidence sex-specific recurrence rates of ASD [autism spectrum disorder] among siblings." In other words, how many boy and girl younger siblings of children with autism were also diagnosed with autism or an ASD and whether the gender/sex of the older diagnosed sibling was an important variable in recurrence risk.

The answers: well, first it's worth noting that that prevalence of ASD came out at ~2%. This was based on administrative health insurance records remember, so is probably quite accurate given that such schemes have to 'pay out' for certain services/provisions as and when autism is diagnosed. Such a figure also adds to other data highlighting this upward trend in cases diagnosed (see here and see here).

Then: "When a male was associated with risk in the family, ASD was diagnosed in 4.2%... of female siblings and 12.9%... of male siblings. When a female was associated with risk in the family, ASD was diagnosed in 7.6%... of female siblings and 16.7%... of male siblings."

You can perhaps see that there were some subtle differences in the autism/ASD recurrence rate according to the sex/gender of the child first diagnosed with autism in a family. The Spectrum review of this paper quotes the lead author saying: "For a girl to emerge with [autism] in the first place indicates that that is a high-risk family" indicating that the appearance of females with autism might mean a greater genetic load is already present in relation to autism risk for example, which then affects subsequent recurrence risk for autism in later born siblings. That is, if one assumes that genes are the be-all-and-end-all of autism risk (see here)...

What else would I like to see in future investigations? Noting the name Isaac Kohane as part of the authorship group of this paper and acknowledging his past contributions to the autism research landscape with a focus on comorbidity and autism (see here) I do wonder if more could be done on that topic with autism recurrence in mind. Y'know, accepting that various psychiatric and somatic comorbidity are 'over-represented' following a diagnosis of autism (see here), a little more information on what else might be recurring alongside autism could provide some important clues about hows-and-whys, particularly bearing in mind that 'autism genes' aren't necessarily just genes for autism (see here)...


[1] Palmer N. et al. Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings. JAMA Pediatrics. 2017. Sept 25.


Monday, 16 October 2017

Vitamin A supplementation and autistic symptoms: hidden away but no significant effect...

I used the words 'hidden away' in the title of this post because I had a bit of a time deciphering the findings reported by Juan Liu and colleagues [1] (open-access) investigating "the role of VA [vitamin A] in the changes of gut microbiota and changes of autism functions in children with ASD [autism spectrum disorder]." Vitamin A by the way, is a fat soluble vitamin involved in various process such as immune function and vision health. There is a darker side to vitamin A however, as safe upper limits have been in place for quite a few years, particularly for pregnant women as a result of potential teratogenic effects.

Suffice to say that after 6 months of VA supplementation - "participants with an insufficient plasma retinol status (<1.05 μmol/L) received VAI [vitamin A intervention?] with a dose of 200,000 IU once orally" - the authors reported seeing no significant changes in autistic signs and symptoms as measured before and after using the Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS). They did however report changes in retinol status (a marker for vitamin A availability) coinciding with supplementation: "The plasma retinol level increased from 0.59 ± 0.19 μmol/L to 0.72 ± 0.20 μmol/L in the group of 64 after 6 months of VA supplementation" and changes in the percentages of vitamin A levels (typical, marginal deficiency, deficient) across their group. I say this however, based on their use of high performance liquid chromatography (HPLC) with photodiode-array detection for assaying for retinol; state-of-the-art about 30 years ago and now superseded by better detection technology such as mass spectrometry...

No mind, Liu et al also looked at "CD38 and acid-related orphan receptor alpha (RORA) mRNA levels" as "autism-related biochemical indicators’ changes" following supplementation. RORA - retinoic acid-related orphan receptor-alpha - has some research history discussed before on this blog (see here). Authors reported that: "After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased" despite the seeming lack of effect on presented autistic symptoms.

Further: "Fresh stool samples were collected from participants who did not receive supplemental probiotics or prebiotics and who were not treated with antibiotics for the previous 1 month." Said poo(p) samples - pre and post-vitamin A supplementation - were analysed alongside food diaries and food frequency behaviours. Authors observed that bacterial species showed changes between the baseline and post-intervention samples; specifically settling on "significant increases in the proportion of Bacteroidetes/Bacteroidales and decreases in Bifidobacterium after the VAI, accompanying significant increases in autism biomarkers, while no significant changes were observed in autism symptoms."

What can we make of these collected findings? Well, whilst vitamin A deficiency is something to look out for among children with autism [2] (see here too) and previous research has indicated "an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids" [3] the lack of a significant behavioural effect from vitamin A supplementation in this case cannot be just glossed over. Yes, this was an open-trial - "we aimed to conduct a placebo-controlled intervention study, but all the participants showed an insufficient VA status and were thus enrolled into the VAI group" - and so has shortcomings but the findings of a lack of significant change across any and all of the autism-related behaviour schedules used is notable. The biological results are a little more interesting; particularly the bacterial findings. But again it wouldn't be difficult to say 'so what?' to such bacterial results given that no corresponding changes in autistic behaviour(s) were noted...


[1] Liu J. et al. Effect of vitamin A supplementation on gut microbiota in children with autism spectrum disorders - a pilot study. BMC Microbiology. 2017; 17: 204.

[2] Chiu M. & Watson S. Xerophthalmia and vitamin A deficiency in an autistic child with a restricted diet. BMJ Case Rep. 2015 Oct 5;2015. pii: bcr2015209413.

[3] Riebold M. et al. All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder. Mol Med. 2011;17(7-8):799-806.


Saturday, 14 October 2017

Bullying and autism: stating the bleedin' obvious...

A short post today to reiterate the 'bleedin' obvious': children diagnosed as being on the autism spectrum are far more likely to be the victim of bullying than perpetrator (see here for a previous blog post on this topic).

This conclusion comes from the paper by Hwang and colleagues [1] based on responses to the Behavior Assessment System for Children: Second Edition (BASC-2) (parental report version). The authors initially reported that "children with ASD [autism spectrum disorder] showed significantly increased risk for bullying involvement compared to community children" potentially indicating that a diagnosis of autism does not somehow shield someone from either being bullied or indeed, participating in bullying behaviour (perpetrator). But... "after controlling for comorbid psychopathology and other demographic factors, increased risks for being perpetrators or victim-perpetrators disappeared while risk for being bullied/teased continued to be significantly elevated." Said 'comorbid psychopathology' included aggression and conduct problems as well as the signs and symptoms of depression potentially accompanying a diagnosis of autism. Indeed, aggression was pretty much linked to every type of bullying behaviour in both autism and control groups...

What's more to say on this topic? Well, further recognition that school in particular, can be a significant source of stress and anxiety for children on the autism spectrum is one thing (and potentially contributory to the stats on school refusal in the context of autism). Indeed, without trying to armchair diagnose nor artificially inflating the seriousness of bullying, I wonder whether quite a few more children on the autism spectrum need to be screened for possible post-traumatic stress disorder (PTSD) in the context of how traumatic bullying can be for a person (see here). In relation also to the point made about aggression being a common variable predicting bullying across the Hwang cohort, I wonder whether more needs to be done more generally in relation to reducing aggression in places like school and thus potentially reducing bullying behaviour more generally?

And whilst on the topic of bullying, it appears that some of the longer term effects of bullying for some might be countered by some kind of resilience (whatever 'resilience' might mean)...


[1] Hwang S. et al. Autism Spectrum Disorder and School Bullying: Who is the Victim? Who is the Perpetrator? J Autism Dev Disord. 2017 Sep 21.


Friday, 13 October 2017

Quarter of kids with autism with iron deficiency but...

Iron (Fe) is something that I've always been a little bit interested in on this blog with specific regards to autism (see here). Outside of the typical 'helping to produce red blood cells' bit, I've always been intrigued by the potential behavioural and cognitive effects following issues with suitable iron supplies. My particular interest in an enzyme that relies on iron as a co-factor (see here) is also worthwhile noting...

A new paper by Serkan Gunes and colleagues [1] (open-access) continues the important theme of iron and autism suggesting that various iron-related parameters might be sub-optimal in relation to the autism spectrum but also with a possible confounding effect of comorbidity in relation to the presence of iron deficiency anemia (IDA) and autism.

Looking at 100 children and young adults diagnosed with an autism spectrum disorder (ASD) and 100 not-autism (I hate the term "healthy controls") controls, researchers surveyed both blood samples and behaviour using a variety of measures. Alongside just having a diagnosis, participants with autism were also subject to various measures covering autistic behaviours, "intellectual evaluation" and various behavioural schedules in-between. Various iron-related parameters were studied: serum ferritin ("as an indicator for ID [iron deficiency] since it is a precursor for ID and represents iron levels in body tissues including brain") and then hemoglobin, hematocrit, iron, ferritin, MCV (mean corpuscular volume), and RDW (red blood cell distribution width).

Results: as per the title of this blog post, 25% of participants fell into the range of iron deficiency (ID). Perhaps a little more seriously, some 13% also presented with iron deficiency anaemia (IDA). This compared with 15% and 6% of the control group respectively. The 'but...' in the title of this post reflects the fact that saying a quarter of children with autism might have ID sounds dramatic but perhaps not so dramatic when it compares with that 15% of controls; hence the lack of significant difference between the groups. Having said that, it is worthwhile noting that controls in this study were not necessarily children and young adults just plucked at random: "For the control group, 100 children (an equal number with patients), who referred to the department [child and adolescent psychiatry department] for counseling about child development, school adjustment and performance, teenage problems, family and friend relations, were recruited."

Then: "Hemoglobin, hematocrit, iron, and MCV (p < 0.05) levels were found to be lower in children with ASD."

Finally, taking into account age (comparing those with autism under 6 years (n=46) with those over 6 years (n=54)) and the presence of learning (intellectual) disability (n=58) vs. those with none (n=42) and autism severity (mild-moderate ASD (n=50) vs. severe ASD (n=50)), some other interesting trends were observed. "Hemoglobin, hematocrit, and MCV (p < 0.05) levels were found to be significantly lower in preschool ASD patients" and "Hemoglobin and hematocrit (p < 0.05) levels were significantly lower in ASD patients with intellectual disability."

What can we conclude from the Gunes paper? Well, I don't want to belittle the various issues with iron detected in either group included for study. If ID or more seriously IDA is detected, remedial measures need to be adopted to correct such issues irrespective of a diagnosis of autism or anything else. Insofar as the relationship(s) between iron parameters and autism, the Gunes papers reiterates that this is likely to be complex and not necessarily just exclusive to autism. Perhaps the most accurate thing I can say is that yet again, a diagnosis of autism or ASD is seemingly protective against nothing when it comes to comorbidity and [preferential] screening is once again implied. Oh, and when it comes to trying to predict those people on the autism spectrum who might be at greatest risk of iron deficiency et al, the findings published by Sidrak and colleagues [2] offer some possible variables: "problems sucking, swallowing or chewing...; poor eating behaviour...; and inadequate amounts of meat, chicken, eggs or fish."


[1] Gunes S. et al. Iron deficiency parameters in autism spectrum disorder: clinical correlates and associated factors. Italian Journal of Pediatrics. 2017; 43: 86.

[2] Sidrak S. et al. Iron deficiency in children with global developmental delay and autism spectrum disorder. J Paediatr Child Health. 2014 May;50(5):356-61.


Thursday, 12 October 2017

Severe mental illness translates into "more sedentary behavior and significantly less physical activity"

The title of this post reflects the findings reported by Davy Vancampfort and colleagues [1] (open-access) who concluded that various diagnoses - "schizophrenia, bipolar disorder or major depressive disorder" - under the label of severe mental illness were associated with decreased physical activity and increased sedentary behaviour(s).

Under the auspice of a "global systematic review and meta-analysis", authors settled on some 70-odd studies that met their search criteria comprising over 35,000 people diagnosed with one of the conditions described and nearly 3000 asymptomatic (asymptomatic for severe mental illness) controls. Vancampfort et al describe assessing for "co-primary outcomes" that "were the mean time (min) per day that people with severe mental illness and healthy controls (in case-control studies) engaged in physical activity, or were sedentary." They found "23 study estimates of physical activity were based on objective measures, three utilized objective and subjective measures and 57 were based on self-report questionnaires"; something important in the context of the technology available to measure activity these days.

Results: Those diagnosed with a severe mental illness (SMI) were "more sedentary than age- and gender-matched controls from the general population, spending a mean of 476 min per day (or almost 8 hours) during waking hours in sedentary behavior." Further: "people with severe mental illness are significantly less physically active and spend only an average of 38.4 min per day in moderate or vigorous physical activity." When tweeting about this article, one of the authors - Brendon Stubbs - also linked to another important paper [2] published on the same day as their own, observing that: "Increasing physical activity is a simple, widely applicable, low cost global strategy that could reduce deaths and CVD [cardiovascular diseasein middle age." It's not difficult to see the connection(s) between the two findings.

"Our data documented that higher body mass index, lower cardiorespiratory fitness, and antidepressant or antipsychotic prescription might constitute barriers for engaging in physical activity." One of the value-added bits to the Vancampfort data were the discussions on some of the barriers to engaging in physical activity in those with SMI. Combined with observations such as: "Those who are single or unemployed, those with a low educational level and men are less physically active" it's not too difficult to see what areas might need to be 'tackled' if physical activity levels are to be improved. Indeed, other data (see here) has even talked about what types of exercise might be best suited to what labels (minus any sweeping generalisations).

And since I've mentioned the topic of depression in this post, I might also draw your attention to another paper recently published by Joseph Firth and colleagues [3] - one of the authors on the Vancampfort paper - talking about how technology might provide a useful backdrop to intervention for depressive symptoms. Specifically how the delivery of smartphone apps might be something useful to consider in the context of depression. Indeed, if one assumes that physical activity levels might also be lower in relation to something like depression, one could forsee a time when one or more smartphone apps might either prompt the need for more physical activity or even potentially offer a tailor-made physical activity schedule complementary to other intervention options...

Music to close and Sammy singing Mr Bojangles...


[1] Vancampfort D. et al. Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta-analysis. World Psychiatry. 2017. Sept 21.

[2] Lear SA. et al. The effect of physical activity on mortality and cardiovascular disease in 130 000 people from 17 high-income, middle-income, and low-income countries: the PURE study. Lancet. 2017. Sept 21.

[3] Firth J. et al. The efficacy of smartphone-based mental health interventions for depressive symptoms: a meta-analysis of randomized controlled trials. World Psychiatry. 2017 Oct;16(3):287-298.