Establishment Journal Nature Refuses Discussion on Autism Gene Project Failure
The authors put their results into perspective – “the population attributable risk ... is estimated to be 3.3%”. This says, in effect, that 96.7% of ASD cannot be attributed to these genetic changes. Moreover, the figure of 3.3% includes ID genes (already excluded) and significance was not adjusted for multiple comparisons.
The paper therefore provides extremely robust evidence that, in all but a few cases, ASD is not a genetic disorder...
By John Stone
The scientific journal Nature has refused publication to a letter from Drs Lorene Amet and Carol Stott in response to the study by the Autism Genome Project Consortium (AGPC, Pinto et al) (HERE ), which was widely publicised as having breakthrough status in the media when it was published on-line in June. The letter echoes and expands upon many criticisms already articulated by Mark Blaxill in Age of Autism (HERE). The Amet/Stott letter shows that so far from having demonstrated the influence of genes in autism the Pinto study illustrates the relatively small contribution of identified abnormalities in all but a very small proportion of cases, leaving the AGPC with the project of conducting ever wider searches for ever more tenuous correlations.The unwillingness of Nature to publish any challenge to the study is morally insupportable.
Sir
Autism Spectrum Disorder (ASD), a previously rare neurodevelopmental condition affects today in the UK one child in 64 (1).
There has been extensive debate on whether ASD has a predominantly genetic or environmental etiology. The three largest genome-wide association studies performed on more than 3000 individuals in total, have however so far failed to detect any specific gene association with any consistency across the studies (2-4). Predicated on a genetic etiology, the most recent study by Pinto et al. 2010 (4) looked at the frequency of rare inherited and de novo copy number variants (CNV). The paper concludes that CNVs are implicated in ASD, highlights the potential role of novel ASD genes including SHANK2, SYNGAP1 and DLGP2.
However, does this study point towards, or away from, a genetic etiology? Although seeming to argue that genetic changes underlie ASD development, careful scrutiny reveals that the paper confirms that ASD is not a predominantly genetic disorder.
Before examining the results of the Pinto et al. publication, the underlying assumption that genetic changes underpin ASD warrants evaluation. The paper states “Some 5-15% of individuals with an Autism Spectrum Disorder (ASD) have an identifiable genetic aetiology corresponding to known single-gene disorders (for example, fragile X syndrome) and chromosomal rearrangement (for example, maternal duplication of 15q11-q13)”, but no reference is provided for this statement. One remarks that the oft-cited twin studies that find high concordance between monozygotic twins do not distinguish between genetic and environmental etiologies – because such twins share an identical in utero and postnatal environment.
Taking the first example – fragile X, associated with mutations at the FMR1 locus – is it true that many ASD individuals have FMR1 mutations?
In the early 80s, when autism prevalence was estimated to be around 5 per 10,000 births (5), as many as 10% of ASD individuals were found to have fragile X (6). In 2005 by contrast, when autism prevalence is much increased, to around 1 in 150 (7), fragile X was encountered in less than 1% of the ASD population (8). In the last few years, in a group of 400 ASD children at the Autism Treatment Trust, only three (i.e. less than 1%) have a known genetic condition; one has fragile X, another has a mutation affecting NF-1 and a third one has partial trisomy of chromosome 15.
Today, therefore, it is strictly incorrect to state that any significant proportion of ASD individuals has “known single-gene disorders”. The vast majority do not.
Turning to the publication by Pinto et al., it will be helpful to look in depth at the results reported and the conclusions that can be justified.
Pinto et al. used a SNP microarray to look at signal intensity (i.e. copy number) across the whole genome, and then assemble these into clusters in which adjoining (genetically linked) markers reiteratively have higher (duplication) or lower (deletion) intensities. This was performed on 1274 ASD cases and 1981 controls of European ancestry.
The first analysis – changes in CNV numbers across the whole genome – apparently found no significant changes. To improve statistical power, Pinto et al. then looked at CNVs encompassing known genes (‘genic CNVs’). This second analysis revealed a significant difference between cases and controls (P = 0.012) although the case:control ratio was only 1.19. Here only deletions were of statistical significance (P=0.008).
The third analysis looked at the sizes of the CNVs. Small CNVs (<500 kb) were significant for deletions only (P=0.004), whereas large CNVs (>500Kb) achieved significance for duplications only (P = 0.007) (uncorrected for multiple analyses).
To further expand on these findings, Pinto et al. introduced several gene lists and analysed them separately. The first gene list was ‘ASD implicated’. This comprises 36 genes and 10 loci “strongly implicated” in ASD: in other words, a list of genes that previous studies have highlighted as being associated with some (rare) cases of ASD. This predominantly comprises the new candidate genes identified in the Pinto et al. study. The second list is ‘intellectual disability’ (ID) – “110 genes and 17 loci implicated in intellectual disability but not yet in ASD” and the third list consists of “ASD candidates including 103 genes from previous studies of common and rare variants”.
The first list of 36 genes selected as autism candidates includes a range of rare genetic disorders, such as Joubert Syndrome (9), Cortical dysplasia-focal epilepsy syndrome (10), Rubinstein-Taybi Syndrome (11) and many other similar conditions that have specific clinical, developmental, morphological and behavioural features that are clearly distinct to that of autism. A significant association between known ASD genes (P = 0.0026) was found but here the association was only with duplications (P = 0.00094) and not with deletions (NS, not significant).
Regarding the second list, the observer will be keenly aware that the category (ID) is suspect on statistical grounds. One does not know how many artificial lists were generated and compared. Other possible lists might include ‘any psychiatric disorder’ (including e.g. anxiety, a common co-morbidity of ASD), ‘any central nervous system disorder’ (including e.g. autoimmune neurodegenerative conditions – immune system anomalies are common in ASD), ‘any childhood disorder’; many other such lists are possible. In the absence of any clarification of how many such analyses, therefore, the Bonferroni correction for multiple comparisons argues that ID must be excluded from further analysis.
Regarding the third list of genes, there was no significant association between ASD and CNVS associated with the candidates ASD genes. This indicates therefore that the Pinto study failed to replicate the findings of predeceasing genome-wide studies.
Interestingly, the Pinto paper identified in 5.7% of ASD cases one or more de novo CNVs, but somehow there is not even a tentative explanation as to the reason for this. Importantly 69% of the control group consisted of females, with a mean age of 39.2 years. This cannot possibly be equivalent to any typical group of ASD subjects, which must be younger and include a larger proportion of males. It must be possible that the de novo CNV rate is associated with the birth age and gender of the patients, which may account for the somewhat subtle and inconsistent changes detected between the two groups.
Despite the very unclear picture emerging from these data, the authors concluded that “Single-occurrence CNV deletions had increased rates in ASD cases over controls, indicating that some could be pathogenic”. Such a statement is premature, particularly given the level of confusion and the absence of a measurement of potential changes in gene expression. DNA copy number variation is a widespread and common phenomenon among humans. It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to copy number. Recent work in breast and ovarian cancer demonstrates an extremely variable penetrance in monozygotic twins to be functionally independently of CNV profiling (12). A deletion or duplication in a selected gene area does not necessarily imply that there is a phenotypical change associated with this variation. Consistently, in the lists of de novo CNVs identified, many deletions or duplications were not found in the affected ASD sibling. The simplest explanation to these findings is therefore that the CNV changes detected are not related to autism.
What is the importance of these findings? The authors put their results into perspective – “the population attributable risk ... is estimated to be 3.3%”. This says, in effect, that 96.7% of ASD cannot be attributed to these genetic changes. Moreover, the figure of 3.3% includes ID genes (already excluded) and significance was not adjusted for multiple comparisons.
The paper therefore provides extremely robust evidence that, in all but a few cases, ASD is not a genetic disorder.
The complexity of ASD dictates that any assessment of the biomedical relevance of the CNV and potential changes in gene expression must be considered in a more strongly integrated context. The early onset of ASD implicates prenatal and perinatal environmental stress (13), and stress itself is known to foster genome mobilization – Barbara McClintock emphasised "the importance of stress in instigating genome modification by mobilizing available cell mechanisms that can restructure genomes” (14). The phenotypic presentation of today’s autism commonly includes regressive features, together with gastro-intestinal and immune abnormalities (15, 16). These must be taken into account in any search for an etiology. Time will tell if the locus duplications identified by Pinto et al. in a minority of ASD cases are found to be, not a cause of ASD, but instead a marker of adverse environmental influences that can lead to ASD development.
References:
1- Baron-Cohen,S., et al. (2009). Prevalence of autism-spectrum conditions: UK school-based population study. The British Journal of Psychiatry 194, 500-509.
2- Wang,K., et al. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528-533.
3- Weiss,L.A., et al.. (2009). A genome-wide linkage and association scan reveals novel loci for autism. Nature 461, 802-808.4- Pinto,D., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature.
5- Croen,L.A., et al. (2002). The changing prevalence of autism in California. J. Autism Dev. Disord. 32, 207-215.
6- Brown,W.T., et al. (1982). Autism is associated with the fragile-X syndrome. J. Autism Dev. Disord. 12, 303-308.
7- Hertz-Picciotto,I., et al. (2006). The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism. Environ. Health Perspect. 114, 1119-1125.
8- Lathe,R. (2009). Fragile X and autism. Autism 13, 194-197.
9- Brancati,F., Dallapiccola,B., and Valente,E.M. (2010). Joubert Syndrome and related disorders. Orphanet. J. Rare. Dis. 5, 20.
10- Fauser,S., et al. (2006). Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients. Brain 129, 1907-1916.
11- Chiang,P.W., Lee,N.C., Chien,N., Hwu,W.L., Spector,E., and Tsai,A.C. (2009). Somatic and germ-line mosaicism in Rubinstein-Taybi syndrome. Am. J. Med. Genet. A 149A, 1463-1467.
12- Lasa,A., Ramon,Y.C., Llort,G., Suela,J., Cigudosa,J.C., Cornet,M., Alonso,C., Barnadas,A., and Baiget,M. (2010). Copy number variations are not modifiers of phenotypic expression in a pair of identical twins carrying a BRCA1 mutation. Breast Cancer Res. Treat.
13- Gillberg,C., and Coleman,M. (1992). The biology of the autistic syndromes (MacKeith Press and Blackwell: Oxford).
14- McClintock, B. (1983). Nobel Lecture: The Significance of Responses of the Genome to Challenge, Nobel Foundation, Stockholm. http://nobelprize.org/nobel_prizes/medicine/laureates/1983/mcclintock-lecture.html.
15- Buie,T., Fuchs,G.J., III, Furuta,G.T., Kooros,K., Levy,J., Lewis,J.D., Wershil,B.K., and Winter,H. (2010). Recommendations for evaluation and treatment of common gastrointestinal problems in children with ASDs. Pediatrics 125 Suppl 1, S19-S29.
16- Amet,L.E., and Line,P. (2010). Autism Syndromes: Clinical issues behind the label. Brit. Med. J. 340, c1127.
Robin;
Since I am one of the people here, I will respond.
Go ahead and pray - oh yes pray - that the American people will continue to be ignorant of vaccines damaging their hypothalmus.
Pray - that the American people continue to feel guilty -- Christian GUILT that they are just glutinuous and lazy and thus they deserve to be a fat diabetic---- and may they never - never catch on that they have been damaged!
Because when the American people do catch on -- it is going to be some really tough times for doctors, and anyone involved in the medical field or government.
Posted by: Benedetta | August 03, 2012 at 12:06 PM
Furthermore (to previous comment), you may note in that link that I stated (in July 2010):
"In my 1993-published theory I indicated conditions in which autism would change from being mainly genetic to being mainly environmental. And exactly that has now happened in.the last 2 decades."
And of course since then there's been that new twin study that confirmed what I said there. So remember that if you want to hear the news before it happens, just let those with the due foresight be your guide.
Posted by: Robin P Clarke (end of comment) | August 03, 2012 at 09:55 AM
Dear People here, It may have escaped your esteemed attentions that on the very same page of the Nature report in question, there was already my own online comment pointing out exactly that point that it proves there is negligible involvement of significant genes in autism. Rather it confirms my point of 20+ years earlier that the causes of autism are various environmental and a large lot of genes rather than just one or two.
My words are still there on that page:
http://www.nature.com/nature/journal/v466/n7304/full/nature09146.html so the censors must be getting lazy.
As for not getting Nature to publish something (as a "publication" rather than online comment), it's long been known that they only publish state-of-the-ignorance drivel, so what's the big deal this time?
Posted by: Robin P Clarke (end of comment) | August 03, 2012 at 09:33 AM
Michael Framson - thanks for citing a perfect example of "rotting fish". Pharma-sponsored clinical "research" has been corrupt for quite some time. I don't know why there have not been more criminal indictments. Pharma CEO's should bear responsibility. Pharma CEO's should be permanently barred from ever submitting claims to MEDICARE/MEDICAID/Tricare.
Here's an interesting article titled, "Have you noticed mainstream health news getting crazier lately?" by Mike Adams on September 24, 2010.
http://www.naturalnews.com/z029837_health_news_mainstream_media.html
"getting crazier lately" No kidding!!!
Actually, "getting crazier" is an understatement. The complicity of the mainstream medical media is not passive. They are an essential operational element of pharma’s agenda. Malice can be inferred. Their publication bias is enormous. Their COIs are too numerous to count.
Posted by: patrons99 | September 24, 2010 at 06:56 PM
Patrons 99, the image of the rotting fish is certainly the graphic representing the state of current medicine and research.
In case you need to read more articles about "rotting fish"
The Deadly Corruption of Clinical Trials
http://motherjones.com/environment/2010/09/dan-markingson-drug-trial-astrazeneca?page=1
Internal correspondence repeatedly refers to Study 15 as a "failed study," and company officials discuss possible ways to spin or bury it. "I am not 100% comfortable with this data being made publicly available at the present time," wrote Richard Lawrence, a senior AstraZeneca official, in 1997. "However I understand that we have little choice...Lisa [Arvanitis, a company physician] has done a great 'smoke-and-mirrors' job." Lawrence referred approvingly to a strategy that he said would "put a positive spin (in terms of safety)
"Thus far, we have buried trials 15, 31, 56," wrote a publications manager in 1999. "The larger issue is how do we face the outside world when they begin to criticize us for suppressing data."
Posted by: michael framson | September 24, 2010 at 03:01 PM
Michael Framson - "Like Martin Walker pointed out: Science is the new politics."
Pharma has co-opted science. The majority of published medical literature over the last three decades can simply not be trusted. The majority of medical journals are effectively operational arms of pharma. Their COIs are too numerous to count.
Again, the image of a rotting fish, which stinks from head to tail, comes to mind.
Posted by: patrons99 | September 24, 2010 at 08:40 AM
To put this in a slightly wider context it is becoming recognised that genetics is a blind alley for medicine but there is too much money involved:
http://www.telegraph.co.uk/science/steve-jones/5189941/One-gene-will-not-reveal-all-lifes-secrets.html
http://www.bmj.com/content/340/bmj.c1156.full
So, every time they fail to find something the search gets wider and more costly, with ever more jobs for the boys and gals. And as with autism in many fields it will also be a distraction from finding out what is really wrong.
Time, then, for GSK and Sanofi to sponsor more chairs in genetics!
Posted by: John Stone | September 24, 2010 at 02:39 AM
All of these science magazines are garbage.
They discuss these wild theories about dinosaurs, that no one could possible ever prove - like did dinosaurs actually love their mates and protect them, and in so doing their offspring were more likly to survive and that way their genes were passed on down to the birds of today! Probably through a retro- virus given to their bird descendents were it jumped cross speicies to us humans and that is why we love our mates.
Then there are the articles on the green movement. The message here is don't make a carbon foot print, don't eat beet eat aspargus instead! Because beef produces more carbon dioxide than flying a plane down to South America to get the aspargus.
And if we don't stop eating beef all extra cow parts will be dumped in the ocean and it will warm it up and make it less salty and then the deep ocean conveyor belt currents will stop and we will go through a 10,000 year ice age.
And when they run out of dinosaur useless theories or green messages they put in things like Monkeys gave rise to malaria.
and make comments like
"It's a fascinating evolutionary question to ask where these human pathogens came from," says evolutionary biologist Paul Sharp of the University of Edinburgh, UK, who worked on the study. "We're now wondering whether a cross-species jump like this could happen again in the future."
Let me answer that for him - oh yes probally in your next vaccine - because that vaccine just might could have a pig virus or two in it, or whats this new talk of a- a- a mouse virus.
Posted by: Benedetta | September 24, 2010 at 12:44 AM
So is the "Journal Nature" pulling a "New England Journal of Medicine"(NEJM)stunt? You know, when you publish garbage, really flawed garbage, that astute and knowledgeable researchers point out the flaws, the journal will not publish the letter which points out precisely the areas that deserve criticism.
Like Martin Walker pointed out: Science is the new politics. NEJM and Journal Nature, the new political party. Vote for us and we will protect your industry.
Posted by: michael framson | September 23, 2010 at 11:14 PM
wonder what Nancy Snyderman is having for dinner? Like to make her eat this!
Posted by: Alison MacNeil | September 23, 2010 at 07:50 PM
Thank you, John Stone, for bringing this letter to our attention, and thank you to these doctors for pointing out the actual results of the multi-decade, multi-million dollar autism gene hunt.
Posted by: JenB | September 23, 2010 at 07:38 PM
Bad genes have been around forever but autism hasn't. from my point of view it takes something to trigger this. its a man made mess.
Posted by: just me | September 23, 2010 at 05:36 PM
This needs to be all over the news:
" in all but a few cases, ASD is not a genetic disorder... "
Teresa, you are right...this should be all over the news...but it won't be:(
Posted by: kathleen | September 23, 2010 at 03:42 PM
Wow! This is huge! Although my hope for redirection of research funds still lives and is reassured by these findings, the immediate impact should be that parents and ASD sufferers can confidently continue to green their environments and bodies, knowing that they are not wasting their time, but putting forth efforts that are more likely to be rewarded then waiting around for genetic research to provide some time of answer to the majority of them. It's just not going to happen. It may be more hopeful for future generations rather than existing ones, but then again, cleaning up does sometimes take more effort than making a mess. At the very least, maybe refocusing on the environment can mitigate and prevent the disease from expanding, even for those already suffering from it.
Posted by: Jenny | September 23, 2010 at 02:24 PM
I'm not even buying the "few cases". I believe autism is man made.
The chickens have come home to roost.
Posted by: Steph M | September 23, 2010 at 02:17 PM
Ran across this the other day. History is always good...
History of Thimerosal and Autism
http://adventuresinautism.blogspot.com/2005/08/beginning-at-beginning.html
Posted by: cmo | September 23, 2010 at 01:50 PM
This needs to be all over the news:
" in all but a few cases, ASD is not a genetic disorder... "
We've known it now it's about time the rest of the world knows it!
Posted by: Teresa Conrick | September 23, 2010 at 11:36 AM