The genetics of autism

Autism and autism spectrum disorders (ASDs) actually represent a rather large continuum of conditions that range from very severe neurodevelopmental delay and abnormalities to the relatively mild. In severe cases, the child is nonverbal and displays a fairly well-characterized set of behaviors, including repetitive behaviors such as “stimming” (for example, hand flapping, making sounds, head rolling, and body rocking.), restricted behavior and focus, ritualistic behavior, and compulsive behaviors. In more mild cases, less severe compulsion, restriction of behavior and focus, and ritualistic behaviors do not necessarily preclude functioning independently in society, but such children and adults may have significant difficulties with social interactions and communication. Because ASDs represent a wide spectrum of neurodevelopmental disorders whose symptoms typically first manifest themselves to parents between the ages of two and three, the idea that vaccines cause autism and ASDs has been startlingly difficult to dislodge and has fueled an anti-vaccine movement, both here in the U.S. and in other developed nations, particularly the U.K. and Australia. This movement has been stubbornly resistant to multiple scientific studies that have failed to find any link between vaccines in autism or the other favorite bogeyman of the anti-vaccine movement, the mercury-containing thimerosal preservative that used to be in many childhood vaccines in the U.S. until the end of 2001. Add to that the rising apparent prevalence of ASDs, and, confusing correlation with causation, the anti-vaccine movement concludes that vaccines must be the reason for the “autism epidemic.”

In reality, autism and ASDs appear to be increasing in prevalence due to diagnostic substition, better screening, and the broadening of the diagnostic criteria that occurred in 1994. Autism prevalence does not appear to be rising, at least not dramatically, at all, as the prevalence of ASDs, when assessed carefully, appears to be similar in adults as it is in children. If the true prevalence rate of autism and ASDs has increased, it has not increased by very much. In reality autism appears to have a major and probably predominant genetic component, and several scientific studies over the last few years have linked autism with various genetic abnormalities. Not surprisingly, given the varied presentation and severity of ASDs, these studies have not managed to identify single genes that produce autism or ASDs with a high degree of penetrance (probability of causing the phenotype if the gene is present). Indeed, one can argue that the state of current evidence is that ASDs are due to multiple genes, perhaps dozens or hundreds. Again, this is not surprising given the heterogeneity of ASD severity, presentation, and symptoms.

One of the more surprising studies supporting a genetic basis for autism appeared to much fanfare in Nature last week. The study by Pinto et al, looks at the functional impact of global rare copy number variation in autism spectrum disorders. Its results are rather surprising in that the large team of investigators (studies of this type take a lot of people to carry out) found that it may be relatively uncommon copy number variations in various genes that lead to the phenotype of autism or ASDs.

Before you can understand what this paper found, you need to know what copy number variation is. In basic genetics and biology classes, many of you probably learned, depending on how long ago you took the courses, that we have two copies of each gene, one on each chromosome, one inherited from the father and one inherited from the mother. The exception is that men have a Y-chromosome instead of a second X chromosome and therefore have only one copy of genes on the X and Y chromosome, the X-linked genes inherited from the mother, the Y-linked genes inherited from the father. Of course, nature is seldom quite so neat, and now that we have powerful tools for sequencing the entire genome and probing its entire DNA to seek out anomalies, we’re finding that things aren’t quite so simple. (Sometimes I marvel that we ever did think things to be that simple.) It turns out that there is considerable variation in the copy numbers of some genes in normal people. This is due to the rare duplication or deletion of a stretch of chromosome during replication. Such errors can leave a person with, for example, one copy on one chromosome and two on another. Although these events are rare for individual stretches of chromosomal DNA, over time and over many generations they can lead to some genes having several. Moreover, there appear to be “hot spots” in various chromosomes that are more prone to duplications or deletions than other regions of DNA.

Because I’m a cancer surgeon and biologist, I’m mostly familiar with variations in gene copy number associated with cancer, and there are many of these. Duplications and amplifications of stretches of DNA are practically the sine qua non of cancer. Often in cancer the amount of gene product in the form of protein that a given gene makes is proportional to the copy number. For instance, in breast cancer, there is a stretch of DNA known as the 8p11-12 amplicon. Basically, it’s a stretch of DNA on the p arm of chromosome 8 that is commonly amplified in breast cancer. This region of chromosome 8 is under active study, and there appear to be a number of candidate oncogenes there. One consequence of our learning about such amplified regions is that a formerly popular (about 30 years ago) and somewhat simplistic idea that single oncogenes would explain carcinogenesis, an idea that was later supplanted by a less simplistic but still too simple idea of multistage carcinogenesis in which a series of mutations in key oncogenes led to cancer. Now we understand that it is many genes that cause cancer. Whole networks of genes are usually perturbed, and, although there are commonalities in many of the networks purturbed among different cancers, the specifics can vary widely from cancer to cancer.

Cancer is one extreme, though, and obviously ASDs are not cancer (or, more appropriately, cancers, given that cancer is not just one disease). ASDs do, however, appear to require multiple genetic changes in order to manifest themselves. Although CNVs are associated with many diseases and conditions, the abnormalities in are not as dramatic or numerous as they are in cancer. In the study under discussion, Pinto et al undertook an a survey of as many CNVs as they could identify in autistic children. Basically, they genotyped 1,275 children with ASD and 1,981 neurotypical controls and compared the frequency of single nucleotide polymorphisms (SNPs) according to the following scheme:


It’s not necessary for you to understand in detail what SNPs are. Basically they are variations in single nucleotides within a gene that are useful because by examining them scientists can estimate CNVs and other genetic variants in various genes. This allows the performance of what is known as a genome wide association study (GWAS), which can look at genetic variation over the entire genome, which is what Pinto et al did using a technique that can look for SNPs in 1.2 million loci per sample. Genetic variations that are more common in people with a disease are said to be associated with that disease. GWAS can be very powerful, but, like much of modern genomic medicine, these studies produce incredible amounts of data, with all the attendant difficulties, both computational and scientific, in interpreting what all the associations that are found may or may not mean.
As the authors note in their introduction, previous attempts at GWAS for autism have identified candidate genetic loci at 5p14.1 and 5p15.2. However, variations in these loci can only account for a relatively small percentage of the heritibility of ASD, hence the desire to examine the entire genome in a large number of children with ASD.

What Pinto et al found was this:

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

One interesting finding was that 5.7% of the CNVs discovered appeared not to be inherited; i.e., they were de novo, meaning, basically, new CNVs. More important, though, was the bioinformatic and systems biology analysis of the CNVs. If there’s one thing that the Human Genome Project has taught us it’s that single genes are rarely that important in disease. Usually, it’s genes that encode for various proteins in discrete functional classes and intracellular signaling pathways, something that can be analyzed by systems biology and network analysis, something I’m increasingly having to do for my cancer research. The result are “bubble diagrams,” which map out various networks and network “hubs” that are important in differences observed between normal and the condition being studied. To come up with such maps and pathway identification requires large numbers of specimens, terrabytes of computer storage space, and a lot of processing power, power that didn’t exist until this decade. In Pinto et al, such an analysis led to the identification of potential new pathways whose function in ASDs may be abnormal compared to the control group. These pathways are mapped out in the following illustration:


Candidate pathways for ASD identified by this method included genes involved with the cytoskeleton and microtubules, as well as genes involved in cell projection and motility, all of which are involved in cell migration. Other candidate pathways included genes involved in cell adhesion. It is not difficult to imagine how defective or altered migration and adhesion of neurons might result in the creation of abnormal neural pathways and thus result in the differences in cognition and behavior observed in ASDs. Of course, I’m putting things very simply. Even if this is true and these pathways are involved in ASDs, we know so little about how neural networks result in cognition and behavior that it will take a very long time and a lot of work to figure out exactly why and how abnormalities in these pathways result in ASDs. The same is true of other potential pathways implicated by these studies. These include GTPase and ras signaling pathways, as well as other kinase pathways. It’s not necessary for the lay reader to understand the full significance of these pathways. I don’t even know the full significance of these pathways in neurons, although I am familiar with them in cancer. Rather, it’s necessary only to know that they are involved in the transmission of signals from protein receptors on the cell surface into the cell, with the result being a number of processes, such as proliferation, migration, and the transmission of signals between neurons, among others.

Almost as important as the candidate pathways implicated by this study that clearly need further study to validate whether they are truly involved in the pathogenesis of ASDs or not are the pathways that were not implicated. One of the major claims of the “autism biomed” movement, the group of quacks who claim that they can treat autism with all manner of woo ranging from chelation therapy to various antioxidants and supplements, is that there are significant defects in pathways involved in countering the effects of oxidative stress, particularly pathways that result in glutathione production. (Glutathione is one of the major scavengers of reactive oxygen species–a.k.a. free radicals–in the cell.) Such claims were prominently featured by the lawyers for the complainants in the Autism Omnibus. Treatments allegedly targeting “detoxification” pathways involving “Glutathione, Cystathionine, Homocysteine, Methionine” figure prominently on the website of many a quack and are a favorite among the “vaccines cause autism” crowd. Don’t ask me how “vaccine injury” somehow causes oxidative stress sufficient to “cause autism.” Anti-vaccine “scientists” have long and convoluted pseudoscientific explanations that are implausible and unconvincing.

Guess what? Not a single one of the common “detoxification” or oxidative stress pathways implicated in ASDs by the “autism biomed” movement showed up in the analysis of the SNP data by Pinto et al. Big surprise, there. Well, not really. Of course, the fact that Pinto et al failed to find any of these pathways in ASDs in their analysis will no doubt be seized upon as “proof” that their analysis is hopelessly flawed. Just you wait. It’s coming. Because everything old is new again when it comes to the anti-vaccine movement I predict that Mark Blaxill will resurrect the same sorts of dubious criticisms of autism genetics studies that he made in this post from a year ago about an autism genetics study that predated Pinto et al:

But if the de novo CNV theory was plausible at one level, it was absurd at another. The genetic mutations the theory proposed (because this was the best the available evidence could support) were completely non-specific. The copy variants were spread widely (even randomly) over the genome, the theory went. No individual mutation was responsible for autism, just the unhappy presence of the wrong one. And these non-specific mutations were not only widely spread, they were virtually undetectable in the infant: no dysmorphic features; generally normal birth and (in many cases development); and the beautiful children we so often see affected by autism.

In other words these CNVs were a case of immaculate mutations.

And it was the perfect new project for the genetics research community. A wide open field of research opportunities. Lots of new money. And a chance to explain past failure away as part of the inexorable march towards genetic understanding.

Ah, yes. Likening science to religion. It’s a favorite canard of cranks of all stripes, be they anti-vaccinationists, creationists, alt-med promoters, 9/11 Truthers, and Holocaust deniers. I’ve heard anti-vaccine zealots refer to “Vaccinianity“; creationists refer to the “Church of Darwin“; and Holocaust deniers refer to “Holocaustianity” (warning: source is a French Holocaust denial website), among others. The intent is obvious: Try to paint the science detested as being faith-based rather than science-based.

The other favored attack, as those of you who read my post earlier today know, is to claim “conflicts of interest,” even when there aren’t any by any reasonable definition of the term. Although Blaxill hadn’t tried his hand at a pseudoscientific deconstruction of this study as of Sunday afternoon, John Stone over at the anti-vaccine propaganda blog Age of Autism has already pulled this gambit. In a post entitled Scherer of Nature Autism Gene Study Fails to Disclose Pharma Funding As Competing Interest, Stone opines:

Prof Stephen Scherer who is the senior author of the autism gene study launched in Nature last week holds the ‘GlaxoSmithKline-CIHR Pathfinder Chair in Genetics and Genomics at the Hospital for Sick Children and University of Toronto. The title used to be ‘GlaxoSmithKline-CIHR Endowed Chair”, GSK being one of the defendant companies in the UK MMR litigation

Mr. Stone is clearly ignorant of just what an endowed chair is. Basically, a company or wealthy donor gives a university a lot of money, and the university sets up an endowed chair using that money. The interest and dividends from the fund used to set up the chair are put at the disposal of the holder of the chair to do research and scholarship as he or she sees fit. The reason such chairs are desirable is because an endowed chair gives a researcher a reliable supply of funding without the need to write grant proposals or a department chair a source of funds for various projects that doesn’t have to come out of the departmental budget. It often allows a researcher to do more exploratory work or a department chair to engage in various research and educational activities by doling out funds from the chair to his faculty, for example, to support pilot projects by young faculty. Once an endowed chair is set up, the donor usually has no say over who gets the chair or how the money for the chair is spent. Claiming that Professor Scherer’s holding the GSK chair at his institution is an insurmountable COI that needed to be reported is, quite simply, ridiculous to anyone in academia who knows what an endowed chair is. Clearly, Mr. Stone does not although one commenter going by the ‘nym of Werdna does try to set Mr. Stone straight. It’s a rare thing indeed on AoA for a commenter to take a blogger to task like that, something that usually only happens when an AoA blogger makes a mistake so egregious even for some AoA readers.

Equally ridiculous is Mr. Stone’s lack of understanding of what a corresponding or first author is on a biomedical research paper:

While Prof Scherer’s departmental colleague Dalila Pinto is listed as lead author of the paper Scherer is listed as ‘correspondence author’ and he identifies himself as ‘senior author’ in Kevin Leitch’s LeftBrain/RightBrain blog.

Here’s a hint for Mr. Stone. The lead author of the paper is an honor usually reserved for the person who had the most to do with designing and doing the research. Most of the time the first author is the person who actually wrote the manuscript. On the other hand, the corresponding author of a scientific paper (at least a biomedical paper) is usually the author listed last or near last. More importantly for Mr. Stone’s criticism, the corresponding author and the senior author are nearly always one in the same, namely the author in whose laboratory and using whose funding the research described in the paper was performed. That’s it. That’s all those terms mean. There’s no inconsistency there. The terms are interchangeable. Mr. Stone would do well to learn a little bit about what he speaks before embarrassing himself so.

I’d be happy to educate him.

Mr. Stone’s follies aside, no doubt when Blaxill or whoever at AoA decides to attack Pinto et al shows up to do it, he’ll repeat the same breathtaking combination of ignorance and binary thinking that he did a year ago. As a pre-emptive rebuttal, I’ll cite popular science blogger P.Z. Myers, who put it well when he pointed out that these things are very complicated. So did Pinto et al:

Our findings provide strong support for the involvement of multiple rare genic CNVs, both genome-wide and at specific loci, in ASD. These findings, similar to those recently described in schizophrenia, suggest that at least some of these ASD CNVs (and the genes that they affect) are under purifying selection. Genes previously implicated in ASD by rare variant findings have pointed to functional themes in ASD pathophysiology. Molecules such as NRXN1, NLGN3/4X and SHANK3, localized presynaptically or at the post-synaptic density (PSD), highlight maturation and function of glutamatergic synapses. Our data reveal that SHANK2, SYNGAP1 and DLGAP2 are new ASD loci that also encode proteins in the PSD. We also found intellectual disability genes to be important in ASD. Furthermore, our functional enrichment map identifies new groups such as GTPase/Ras, effectively expanding both the number and connectivity of modules that may be involved in ASD. The next step will be to relate defects or patterns of alterations in these groups to ASD endophenotypes. The combined identification of higher-penetrance rare variants and new biological pathways, including those identified in this study, may broaden the targets amenable to genetic testing and therapeutic intervention.

The problem is that none of this sort of research is easy, and none of it is likely to result in effective treatments for ASDs very soon. Autism quacks and anti-vaccine zealots, however, can’t accept this. Again, like Blaxill, they demonstrate binary thinking. If a study doesn’t find a single, clear-cut gene or small set of genes causing autism or ASDs 100% of the time, then to them almost invariably the study is crap, autism is not genetic in origin, and vaccines (or other “environmental factors”–not vaccines, you know, nudge, nudge, wink, wink) cause autism. They also seem completely oblivious to developmental biology. It bothers them that a child with ASD appears normal at birth and then only manifests symptoms between the ages of 2 and 4. Anti-vaccine zealots who attack genetic linkage studies will frequently point this out as though this observation is a slam dunk argument against a genetic etiology for autism. Development proceeds, however, according to predictable, sequential steps that are under genetic control, and genetic variations and abnormalities can have a profound impact on development that may not manifest itself until previous parts of the developmental program are complete. For example, Tay-Sachs disease is one of thoes rare diseases for which a single gene is the known cause. Babies with Tay-Sachs usually appear normal at birth and develop normally for the first six months of life. Then the neurologic deterioration begins. There are also a number of inborn errors of metabolism that don’t manifest themselves at birth. In other words, it’s not unusual for purely genetic diseases to exhibit delayed manifestation of symptoms. Otherwise, why would we need to test for phenylketonuria (PKU) shortly after birth?

Antivaccine zealots also seem unable to understand that most chronic diseases and conditions with a strong genetic component are due to changes in activity of multiple genes, sometimes many genes. Due to functional redundancy in our cells, there are also often multiple abnormalities that can produce similar phenotypes; it is therefore not surprising that there might be many different gene abnormalities that contribute to ASDs. Systems biology gives us the tools to start to understand these exceedingly complex processes, as Pinto et al did in the study under discussion and as my collaborators try to do for cancer. The problem is that biology is really complex. Frustratingly to those waiting for treatments, it is far more complex than even scientists realized before the Human Genome Project and the dawn of genomic medicine.

While it is possible–even likely–that there is an environmental component to ASDs, the evidence to date has not convincingly implicated any, except for, ironically enough given how anti-vaccine zealots believe that the MMR vaccine causes autism, maternal rubella infection while the fetus is still in utero, as a cause of autism. Moreover, as P.Z. pointed out, no transient exposure or exposures to an external agent (such as a vaccine) is known to be able to produce such a consistent pattern of gene duplications and deletions in human cells like the sets detected in Pinto et al. Thus far, the preponderance of evidence points to primarily a genetic cause for autism and ASDs, and Pinto et al is another solid study supporting a genetic basis for autism. It also suggests potential cell signaling pathways that might be abnormal in autism and thus targets for therapeutic intervention. That’s all we can ask of such a study. It does not rule out an environmental component, although this study is not consistent with vaccines as an etiology of autism. More importantly, it has failed to provide any validating evidence for the frequently claimed abnormalities touted by autism biomeddlers, abnormalities allegedly targeted by all manner of quack nostroms, from chelation therapy to antioxidants to hyperbaric oxygen to “detoxification.”

Now remains the hard work of validating and replicating these findings and then figuring out which pathways can be targeted for therapy. What I’m afraid of now is that the quacks will look at the pathways identified by Pinto et al and try to come up with new pseudoscientific “biomed treatments” for autism based on these results, after (of course) “showing” how vaccine “injury” can create these same CNVs in children. It wouldn’t surprise me if I were to see this sort of “science” presented at Autism One next year.

On the other hand, maybe not. For quacks to try to use the results of Pinto et al to “treat” autism, they’d first have to accept the results of the study.


Pinto, D., Pagnamenta, A., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T., Correia, C., Abrahams, B., Almeida, J., Bacchelli, E., Bader, G., Bailey, A., Baird, G., Battaglia, A., Berney, T., Bolshakova, N., Bölte, S., Bolton, P., Bourgeron, T., Brennan, S., Brian, J., Bryson, S., Carson, A., Casallo, G., Casey, J., Chung, B., Cochrane, L., Corsello, C., Crawford, E., Crossett, A., Cytrynbaum, C., Dawson, G., de Jonge, M., Delorme, R., Drmic, I., Duketis, E., Duque, F., Estes, A., Farrar, P., Fernandez, B., Folstein, S., Fombonne, E., Freitag, C., Gilbert, J., Gillberg, C., Glessner, J., Goldberg, J., Green, A., Green, J., Guter, S., Hakonarson, H., Heron, E., Hill, M., Holt, R., Howe, J., Hughes, G., Hus, V., Igliozzi, R., Kim, C., Klauck, S., Kolevzon, A., Korvatska, O., Kustanovich, V., Lajonchere, C., Lamb, J., Laskawiec, M., Leboyer, M., Le Couteur, A., Leventhal, B., Lionel, A., Liu, X., Lord, C., Lotspeich, L., Lund, S., Maestrini, E., Mahoney, W., Mantoulan, C., Marshall, C., McConachie, H., McDougle, C., McGrath, J., McMahon, W., Merikangas, A., Migita, O., Minshew, N., Mirza, G., Munson, J., Nelson, S., Noakes, C., Noor, A., Nygren, G., Oliveira, G., Papanikolaou, K., Parr, J., Parrini, B., Paton, T., Pickles, A., Pilorge, M., Piven, J., Ponting, C., Posey, D., Poustka, A., Poustka, F., Prasad, A., Ragoussis, J., Renshaw, K., Rickaby, J., Roberts, W., Roeder, K., Roge, B., Rutter, M., Bierut, L., Rice, J., Salt, J., Sansom, K., Sato, D., Segurado, R., Sequeira, A., Senman, L., Shah, N., Sheffield, V., Soorya, L., Sousa, I., Stein, O., Sykes, N., Stoppioni, V., Strawbridge, C., Tancredi, R., Tansey, K., Thiruvahindrapduram, B., Thompson, A., Thomson, S., Tryfon, A., Tsiantis, J., Van Engeland, H., Vincent, J., Volkmar, F., Wallace, S., Wang, K., Wang, Z., Wassink, T., Webber, C., Weksberg, R., Wing, K., Wittemeyer, K., Wood, S., Wu, J., Yaspan, B., Zurawiecki, D., Zwaigenbaum, L., Buxbaum, J., Cantor, R., Cook, E., Coon, H., Cuccaro, M., Devlin, B., Ennis, S., Gallagher, L., Geschwind, D., Gill, M., Haines, J., Hallmayer, J., Miller, J., Monaco, A., Nurnberger Jr, J., Paterson, A., Pericak-Vance, M., Schellenberg, G., Szatmari, P., Vicente, A., Vieland, V., Wijsman, E., Scherer, S., Sutcliffe, J., & Betancur, C. (2010). Functional impact of global rare copy number variation in autism spectrum disorders Nature DOI: 10.1038/nature09146

Posted in: Neuroscience/Mental Health, Science and Medicine, Vaccines

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49 thoughts on “The genetics of autism

  1. kwombles says:

    I noticed yesterday that, of course, Stone and AoA couldn’t deal with the science of it. I looked around at the coverage in general and wrote on it at Countering. Why argue the science when it’s so much easier not to? Now they’re onto thinking autistic children are deadly white and won’t tan and it’s proof that it’s the mercury in the shots. Sigh.

  2. passionlessDrone says:

    Hello friends –

    Nice write up, very similar to another one I read on Friday. I entered that discussion, got some nice responses, but got caught up in the real world and it looks to have deteriorated over there. Maybe I can find someone else to help me out. (?)

    What left me a bit confused about this study was the seemingly small number of CNVs that affected genes and the number of children with CNVs that were actually found in this study. I’m thinking this is due to a misunderstanding on my part as to the real process of ‘sequencing the entire genome and probing its entire DNA to seek out anomalies’.

    My thoughts were, they scanned the genetic sequence of roughly 2,000 people, half with autism, and half without. From there, they compared their gemones against one another looking for deletions or duplications. Is that incorrect?

    Or is it more like they scanned all participants, and then compared them all against another, common data set to look for irregularities?

    Potentially, therefore, if this common data set didn’t have CNVs present to look for, we then, could sequence the entire genome, find CNVs affecting genes in ~ 10% of our population, and still come away confident that there are likely other, unknown CNVs in the other 90% of the autism population that are contributing. (?) I guess I’m struggling to see how we build a common set of CNVs, to use as a datasource if every human has a couple of million unique CNVs. But if we compared the two groups together, I’d think we should have seen a greater driving force for a condition that is primarily mediated through genetics. Is our cut off rate and /or qa process potentially filtering out information of interest?

    I’m also curious why this is a surprising finding, honestly. Considering this was undertaken precisely because other types of analysis had largely failed to find the types of associations we’d expect, weren’t these types of differences the only other place genetics could be playing a part?

    Finally, is it really any more accurate to say that, for example, SYNGAP1is likely a novel candidate any more than anything else found in the study? I say this because it looks like SYNGAP1was only disrupted in one individual in the case group. Isn’t every gene touched by a CNV in the case group a novel finding? And the flip side of this would be, does anyone know if any previously implicated genes were hit by CNVs in this study?

    Any insight is appreciated.

    – pD

  3. I’m going to do my Barbie imitation. “Genetics is Hard!”

    Awhile back we had a CMA done for my son. There was some suspicion that the two cranial-facial differences he has may indicate a genetic syndrome.

    I spent many hours reading up on genetics and syndromes while waiting for the results. Normally reading up on other therapies (surgery, devises and speech therapy) yields some helpful information to me, even though I am a layman. Not the case this time. I only made myself way more anxious.

    I guess my point is, I won’t be surprised if this paper causes ALOT of confusion and anxiety in some parents of children with autism.

  4. Watcher says:

    @ Michelle

    I guess, I don’t understand how this new information would make one more anxious?

  5. Wow. This is really fascinating. It’s awesome to have a solid scientific analysis of genetic causes to present to the anti-vaccine crowd.

    Micheleinmichigan: Are there craniofacial differences related to ASD? If so, it seems to me that an osteological analysis of historical human remains might indicate historical (pre-vaccine invention) rates of ASD. Of course that assumes ASD isn’t a recently emerging mutation/s.

  6. Anthroplogist Underground – No, I didn’t mean to imply any relationship between ASD and craniofacial differences. Sorry to be unclear. The relationship with my son to the article is tangential. Only that he was having genetic testing done, not that we suspected autism.

    As far as I know, there are a few (of many) craniofacial syndromes that have an elevated risk of developmental delays, Velio-cardio-facial syndrome for instance, but I’m not aware of any that have an elevated risk of ASD. But, I’m not an expert.

  7. Matthew Roman says:

    Looks like these guys just opened the door to a LOT more research. Anyone else have to consciously suppress the term ‘trigeminal nerve’ while reading this? (anyone?… cricket… cricket… )

    This article pretty much changed my view on ASDs. I knew the evidence pointed towards genetic abnormalities… but I had no idea before this of the complexity, abundance and the fact that they were copy number variants. Thanks again for a great article about one of skepticisms most front line topics.

  8. Watcher – That’s an excellent question, that I’m not sure I can answer. My attempt would be, from a scientists perspective more information is good. From a parents perspective is can be scary, particularly when you don’t understand the majority of it. I think at the time that I was looking into the genetic syndrome information, my gut reactions was “Oh my god, look at all the things that can go wrong if my sons genes are flawed. What’s going to happen? Is his sight, immune system, growth going to fail?

    So maybe that was the thing with genetics that made me anxious, the question of what result of the genetic difference we hadn’t seen yet.

    So from a science perspective “It is not difficult to imagine how defective or altered migration and adhesion of neurons might result in the creation of abnormal neural pathways” is interesting and may gives you ideas of therapy. From a parents perspective it sounds ominous.

    But, maybe that’s just me. I can’t speak for all parents.

  9. “So maybe that was the thing with genetics that made me anxious, the question of what result of the genetic difference we hadn’t seen yet.”

    For accuracy this should have read “what result of a potential genetic difference we hadn’t seen yet.

  10. Oh well, my last comment makes no sense without the previous one that is in moderation limbo.

  11. Micheleinmichigan: Thanks for the clarification.

    Now that I’m obsessing about osteological markers of ASD: if the neurological structure is physically different, would it be measurable/visible in endocranial casts in historical remains?

  12. WilliamLawrenceUtridge says:

    There is one physical marker of autism I believe – they tend to, on average, have a greater cranial circumference (i.e. big heads).

  13. Okay – I give up. I reposting the comment that’s in moderation, with the needed edits.


    Watcher – That’s an excellent question, that I’m not sure I can answer. My attempt would be, from a scientists perspective more information is good. From a parents perspective is can be scary, particularly when you don’t understand the majority of it. I think at the time that I was looking into the genetic syndrome information, my gut reactions was “Oh my god, look at all the things that can go wrong if my sons genes are flawed. What’s going to happen? Is his sight, immune system, growth going to fail?

    So maybe that was the thing with genetics that made me anxious, the question of what result of a potential genetic difference we hadn’t seen yet.

    So from a science perspective “It is not difficult to imagine how defective or altered migration and adhesion of neurons might result in the creation of abnormal neural pathways” is interesting and may gives you ideas of therapy. From a parents perspective it sounds ominous.

    But, maybe that’s just me. I can’t speak for all parents.

  14. pmoran says:

    David, all this is hard for me, too, after ten years out of medicine, and I am applying the “what do I really want to know?” rule.

    What is the likelihood of their being some single “parent” genetic abnormality that enables or facilitates all the others at vulnerable points in the genome? Or would such a thing have definitely been revealed by this kind of data?

  15. E says:

    Speaking of autism…

    Here’s quite the example of someone whose senseless jammering includes some astoundingly ignorant words to describe one particular autistic child he encountered. Actually, the guy is Brady Hurst and I wish I could say he was acting in rare form, but that wouldn’t be true; he’s acting pretty average:

    ~ To belittle is to be little ~

    In case anyone couldn’t bear to listen and missed what I’m specifically referring to, I’ll quote two pieces of Brady Hurst’s own small-minded verbiage here:

    – “The kid won’t even talk, ya know, he sits and plays with one toy and that’s it, he doesn’t talk to anyone, right, so…”

    – “This kid was really messed up…”

    (Is there a suggestion box? Perhaps you could make a section called, “Quote Your Favorite Quack.”)

  16. MS, MT(ASCP) says:

    I downloaded and read this paper this week-end, and it was very interesting. Some of it is over my head, but I, too, am familiar with the ras/raf and GPCR signaling pathways. My MS seminar was on the genetics of ASDs and the role that system biology could play in figuring out the relationship between the implicated genes and the phenotype. This paper confirmed some of what I said in 2008.

    My son was diagnosed with AS a few years ago, and we had him tested last year. It turns out he has a CNV, a heterozygous deletion of ~800 kb in 1q21.1 . As a scientist, I understood what that meant, and immediately went to NCBI to see what genes were involved. As a parent, I can appreciate how such information can be frightening. The problem that we in the biochem/molecular biology field have had is making wonderful discoveries of SNPs and CNVs, but not knowing what impact they have on the patient’s phenotype and thus care. We have been close to losing the medical community’s support for such research and information because they didn’t know what to do with it. If we can’t explain it to clinicians, how can we expect the parents of affected children to understand and accept that information?

    The key to keeping this kind of information relevant is to keep studying, and make in clear that the picture is very complicated and requires a lot of patience. The field of epigenetics and the impact of CNVs were very new when I got my MS, and I’ve been trying to keep up since. I can appreciate the desire for quick fixes and answers that indicate certainty, but that cannot be an excuse for lying to ourselves and others to avoid frightening information and frustration over incremental progress. We have also battled our school system for years over services for my son, and if I were of a non-scientific mind, I might embrace alt med in the face of lip-service to institutional support, and in the absence of any real effort to help him catch up.

    On a scientific level, this paper helps push our knowledge forward on the causes of ASDs. On a personal level, I can only hope that we can translate that into something meaningful to parents who look longingly at the confidence displayed by the alt med supporters.

  17. patienz says:

    @micheleinmichigan: You wrote: “No, I didn’t mean to imply any relationship between ASD and craniofacial differences.”

    Actually, the relationship of ASD to minor physical abnormalities such as craniofacial dysmorphologies provides further evidence that ASD begins months before the first exposure to a vaccine, since these changes occur early in gestation. You might be interested in a recent paper and in an abstract from the last IMFAR meeting:

  18. patienz says:

    You might be interested in a response from Milos to John Stone’s cry of “conflict of interest” in the AoA echo chamber. Since such responses tend to disappear, I’ll take the liberty of quoting it:

    1) There is no association between Professor Scherer and GSK. He receives no money from them. He is not beholden to them. He has nothing to declare.

    2) I don’t know if you were confused, but your entire article attempts to insinuate that because one senior author has an endowed chair which has GSK in its name, the study is somehow corrupted, or was done for nefarious purposes.

    Let me be perfectly blunt.

    Like many other scientists, I have chosen a poorly-paid academic career over pharma industry (I have had offers that would triple my pay). This is not that uncommon of a choice: independence and meaning over money.

    If I had an inkling – a barest inkling – that a pharma company was endangering the lives of children, I would fire from all available barrels. Pretty much all of my colleagues would do the same.

    Yet, you and many people on this blog believe (unshakeably) that we are all either blind idiots, or we are laughing all the way to the bank with bags of pharma money over our shoulders.

    This is deeply insulting.

    You have, in this article, based on nothing but the NAME of an ENDOWED CHAIR, besmirched the reputation of over a hundred hard working, dedicated people, who are spending their lives trying to figure out the roots of the disease that affects so many.

    You should support this study. Ok, fine, unlike anyone in the field you believe that vaccines cause autism. You could interpret the study as “identifying genes that make children susceptible to vaccine injury”, and try to make sense of results in that light.

    But no. Instead you have chosen to insult the entire field. Again.

    3) No single CNV correlation is dramatic, this is true. But data like this is sorely needed to make sense of what makes children vulnerable, and can help us predict where to focus our future efforts.

    4) Known genetic syndromes (many of them metabolic) account firmly for 20% of autism cases. There is high confidence for at least another 20%, just based on heritability studies alone. This is before we even start talking about copy number variants.

    But this is beside the point. The main point is #2 above.

  19. RE skeletal abnormalities, WLU and Patienz: I’m really looking forward to checking out the links. Thanks for taking the time to post them!

  20. Werdna says:

    Sadly I’m not your typical AoAer. So I’m not probably the best litmus for determining the depth of Mr. Stones nonsense. (If people hunt around you can find one post full of stupid by me – which I explained in an overlong post on Orac’s blog).

  21. patienz – Interesting links. When referring to craniofacial differences I was thinking primarily of more severe malformations, such as Cleft lip and Palate, Craniosynostosis, Hemifacial Microsomia or Microtia, than the ones referred to in these documents.

    I didn’t realize that science was considering more subtle variations, although considering the usefulness of markers for other disorders such as cafe-au-lait spots for neurofibromatosis, it makes sense that they would.


  22. daedalus2u says:

    I don’t think that there is a genetic “cause” of autism, my conceptualization is that all humans have some ASD traits and are more or less on an autism spectrum, that being on the autism spectrum is a fundamental human trait, the trade-off of a “theory of mind” for a “theory of reality”. I have a whole blog post about that.

    There are two broad categories of autism, the type that occurs in families, and the type that occurs in single individuals with no other affected family members. The singleton type is the type characterized by dysmorphic features and de novo mutations. Familial ASDs are not characterized by dysmorphic features and have much more complex genetics. Usually there is no obvious deletion or duplication, and no single gene accounts for more than a few percent of the propensity.

    The genetic tests that are done are done using blood cells (usually). Blood cells DNA is not necessarily copied with as high fidelity as is genomic DNA of cells that divided and differentiated in utero (as nerve cells did). We know that blood cells do accumulate mutations (that is what leukemia is).

    My nomenclature preference is to differentiate between “autism” (which I consider to be due to neuroanatomy developed in utero), and “autism-like” which occurs due to things that happen after birth. Rett Syndrome is “autism-like” because it occurs due to the deletion of the MeCP2 gene, which causes aberrant readout of methylated DNA. In mouse models, the symptoms of RS are completely recapitulated by turn-off of the MeCP2 gene, and the phenotype is completely rescued by turning MeCP2 back on. I think the autism-like symptoms of RS are due to the metabolic stress of mosaic individuals (females have 2 X chromosomes, one is turned off, MeCP2 is on the X chromosome) with different readout of epigenetically programmed DNA. The cells are not “in sync”, and may even be working at cross purposes. This causes metabolic stress, that causes low NO, low NO causes autism-like symptoms.

    Even if so many different DNA copy number variations do cause autism-like conditions, what is the physiology? What is the final common pathway that causes a very large variety of DNA deletions and duplications to specifically result in autism-like symptoms? The symptoms are common, there must be a common pathway that causes physiology to behave in these common patterns. I think that final common pathway is low NO, which explains both the in utero neurodevelopment and also the ongoing autism-like symptoms.

  23. daedalus2u – “The genetic tests that are done are done using blood cells (usually). Blood cells DNA is not necessarily copied with as high fidelity as is genomic DNA of cells that divided and differentiated in utero (as nerve cells did). We know that blood cells do accumulate mutations (that is what leukemia is).”

    I was told by our Pediatric Geneticist that the Chromosomal Microarray Analysis done from a blood test is a very accurate way to detect genetic abnormalities. If I am reading you correctly, you seem to believe otherwise. I’d be curious as to sources you might have regarding this.

  24. Calli Arcale says:


    There is one physical marker of autism I believe – they tend to, on average, have a greater cranial circumference (i.e. big heads).

    Correct, though the reason is not understood.

    Anecdotal evidence: large heads and learning disorders run in my family. I have a larger than average head, and have ADD. My daughter has a larger than average head, and has PDD-NOS. (This is more obvious in me, as I am shorter than average, while my daughter is taller than average. Her head is close to being proportional for her height, though not her age.)

  25. MS, MT(ASCP) says:

    I have extracted high quality genomic DNA from white blood cells (red cells do not contain DNA) and performed SNP detection on that DNA. The assertion that high quality DNA cannot be extracted from red cells is false. White blood cell DNA is copied with the same high fidelity as body cell DNA because they both use the same copying mechanisms.

  26. daedalus2u says:

    Michelleinmichigan, I am not disputing the use of blood cells for many types of genetic testing, but copy number variation is a subtle type of testing.

    Most genetic testing is for a complete deletion of the gene, or for the presence of a gene with a different sequence. Those are easy to look for. Distinguishing between if there is one copy or two or three is more challenging.

    Blood cells are derived from a smallish population of blood stem cells which divide many more times than the cells that comprise the CNS. Most of the DNA in blood cells is not needed for them to do the tasks that physiology assigns them to do. Deletion of non-necessary genes would have no impact on health or function of blood cells, so it may be more common than is appreciated. Different disease states may accelerate the generation of copy number variations in blood cells.

    I don’t think that it has been established if copy number does not change over a person’s lifespan. Presumably most of them are de novo, so they either happened during gamete formation, during fertilization, or during cell division. We know that somatic cells do experience genetic changes. Most of them don’t matter because most somatic cells don’t need to express all the DNA. There are reports of increased somatic mutations as people age, there is even some thought that might be the mechanism for aging. If so, then subclinical somatic cell DNA degradation might be expected with some frequency.

    Leukemia has a certain incidence (~1% over a lifetime). Leukemia is a genetic change in blood stem cells, I presume deletion of certain leukemia suppressor genes. Deletion of genes other than leukemia suppressor gene won’t show up unless looked for because those cells will die or not cause leukemia. If there are 15 leukemia suppressor genes, and there is ~1% chance that one of these will be deleted over a lifetime and cause leukemia, or about a 0.07% chance of a specific leukemia suppressor gene being deleted. Presumably other genes are deleted just as frequently. Since there are ~20,000 genes, over a lifetime it is possible that on average ~14 genes could be deleted in blood cells. Since the incidence is a lot higher toward the end of life, maybe gene deletion is too. I don’t think it would be unreasonable to expect some basal level of copy number variation in blood cells.

    I am not saying that copy number variation is not important, but that the results to me are not compelling. There is also this very large study which concludes that copy number variation is unlikely to be important in major diseases.

    Even if copy number variations are associated with autism, what is the mechanism? Association does not mean causation. Autism is characterized by increased oxidative stress. Oxidative stress does increase DNA damage. Is the copy number variation a cause or an effect of autism? Exposure to some things (benzene for example) does increase the incidence of leukemia. This demonstrates that blood stem cell are sensitive to some genotoxic effects of some agents. The incidence of leukemia increases with age, demonstrating that what ever genotoxic effects of age there are, they affect blood stem cells.

  27. passionlessDrone says:

    Hi Daedulus2u –

    Most genetic testing is for a complete deletion of the gene, or for the presence of a gene with a different sequence. Those are easy to look for. Distinguishing between if there is one copy or two or three is more challenging.

    Would you be willing to go into more detail as to why this is more challenging?

    Blood cells are derived from a smallish population of blood stem cells which divide many more times than the cells that comprise the CNS. Most of the DNA in blood cells is not needed for them to do the tasks that physiology assigns them to do. Deletion of non-necessary genes would have no impact on health or function of blood cells, so it may be more common than is appreciated. Different disease states may accelerate the generation of copy number variations in blood cells.

    This is a very interesting point.

    I am consistently impressed with your posts. Very nicely done.

    – pD

  28. David Gorski on autism and oxidative stress:
    “One of the major claims of the “autism biomed” movement, the group of quacks who claim that they can treat autism with all manner of woo ranging from chelation therapy to various antioxidants and supplements, is that there are significant defects in pathways involved in countering the effects of oxidative stress, particularly pathways that result in glutathione production.
    […] Treatments allegedly targeting “detoxification” pathways involving “Glutathione, Cystathionine, Homocysteine, Methionine” figure prominently on the website of many a quack … .

    Guess what? Not a single one of the common “detoxification” or oxidative stress pathways implicated in ASDs by the “autism biomed” movement showed up in the analysis of the SNP data by Pinto et al.”

    daedalus2u on autism and oxidative stress:
    “Autism is characterized by increased oxidative stress.”

    daedalus2u, I like you a lot. But I believe this statement is a hypothesis, not a fact, and not currently supported by any evidence.

  29. Daedalus2u – the link you provided says this in the summary.

    “We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn’s disease, HLA for Crohn’s disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.”

    I would read the conclusion to be that the study of “common CNVs” are redundant to the study of SNP based studies.

    To me it seems that “copy number variation is unlikely to be important in major diseases.” overstates that conclusion.

    Like I said before I find genetics very confusing, But just from a layman’s perspective it seems like a contradiction when Dr. Gorski’s article talks at length about the study of CNV’s in cancer research and then you suggest that they are unlikely to be important in major disease.

    Do a google search for CNV’s and one finds that quite a bit of effort is being put forth to research in CNV’s relationship to various disorders. Why would that be if it’s unlikely to be important?

    Is it the difference between “common CNV’s” and uncommon? How about the difference between CNVs that seem unrelated to disorders and one’s that appear to be associated with certain disorders?

    I’m sure that I am over simplifying and venturing beyond my comprehension level. But, my curiosity has gotten the better of me.

  30. ejwillingham says:

    I think that CNVs offer a good avenue of pursuit as a feasible explanation for something that has such a variable phenotype as what we now group as ASDs. I blogged CNVs in December 2009 as holding such promise:

    What this Nature paper highlights for me more than anything else is that we can’t expect identification of a single gene or simple explanation or single mechanism for autism, and CNVs hold the promise of a complexity matching what we call “the spectrum.” The saying in autism circles is that if you’ve met one autistic person, you’ve met one autistic person. Translate that to a unique CNV fingerprint involving a specific suite of pathways common to autism in general, and you’ve got a reasonable hypothesis to work with. Finally.

  31. passionlessDrone says:

    Hi Harriet Hall –

    daedalus2u, I like you a lot. But I believe this statement is a hypothesis, not a fact, and not currently supported by any evidence.

    This is a clear illustration of what happens when you rely on David Gorski for your information about autism.

    Porphyrinuria in Korean children with autism: correlation with oxidative stress [PMID: 20391113]

    Oxidative stress in Egyptian children with autism: relation to autoimmunity [PMID: 20036015]

    Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children [PMID: 19781542]

    Sera from children with autism alter proliferation of human neuronal progenitor cells exposed to oxidation [PMID: 19526302]

    Plasma concentrations of selected antioxidants in autistic children and adolescents [19507654]

    Systemic oxidative stress in classic Rett syndrome [PMID: 19464363]

    Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism [PMID: 19357934]

    Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children [PMID: 19306862 ]

    The neurobiology of autism [PMID: 17919129]

    Altered vascular phenotype in autism: correlation with oxidative stress [PMID: 16908745]

    There are many more, but do we really need to post them? Not linking for spam filtering concerns.

    How do we move forward?

    Perhaps the lack of a CNV in relation to oxidative stress in the 10% of children with CNVs found is representative of the rest of the autism population, and there are no genetic mutations that would predispose an individual to oxidative stress. This would seem to be implied by Mr. Gorski’s statements regarding the lack of a finding in this study.

    What then? One possibility is that all of these studies on oxidative stress are wrong in exactly the same way, and we should use the finding above, which failed to find a CNV in 90% of the sample set, as evidence as to why this might be the case.

    Or, alternatively, oxidative stress is playing a part in autism, and the forces that are playing a part are entirely environmental. If, after all, this study is sufficient for us to write off any genes not identified within it, this would be a logical choice.

    Or, we might consider that the findings in Nature while quite interesting, are insufficient grounds on which to draw sweeping conclusions, no matter how well the soundbyte plays in peoria.

    – pD

  32. ejwillingham – Thanks for the link. Very interesting write-up regarding CNVs and autism – schizophrenia and quite user friendly to the layman. Thanks.

    If you happen to read this, I was curious if you saw any indications that the CNVs in schizophrenia were de nuvo. I’ve heard of a possible correlation between being exposed to some flu viruses in utero and schizophrenia.

  33. daedalus2u says:

    Michelle, schizophrenia caused by exposure to flu virus in utero is incompatible with a CNV (or any genetic) causal mechanism.

    People may argue that there is a “two-hit” mechanism, exposure to virus and CNV, but by what physiology those “two-hits” could possibly interact to produce schizophrenia is completely unknown.

  34. daedalus2u,

    Various things that raise the likelihood of receiving a schizophrenia diagnosis at some point:
    – Being born in the city, or in winter or spring. (Low Vitamin D is a proposed mechanism.)
    – Fetal alcohol syndrome, or anything else that might interfere with fetal development such as malnutrition.
    – Being related to someone with schizophrenia (identical twin > parent or other sibling > aunt, uncle, grandparent).
    – Social adversity, stressful life events, episodes of maltreatment.
    – Smoking dope.

    (This is a very incomplete list and in random order.)

    There is no special reason to assert that only one of the many identified risk factors can be real; that if genetics raise the risk of getting a schizophrenia diagnosis then FAS cannot, for instance. If all these different factors can raise risk, then maybe schizophrenia is complicated. Maybe it’s more than one thing.

  35. daedalus2u says:

    Alison, or maybe all of these different things affect a final common pathway that is the actual “cause” of schizophrenia.

    Sort of like the way that eating too much rice causes one type of obesity, eating too much bread causes another type, eating too many happy meals cause another, eating too much chocolate causes another, drinking too much alcohol causes another.

    We don’t divide obesity into different diseases depending on what type of food is eaten in exces because we understand the final common pathway of obesity is too many calories consumed with the excess stored as depot fat.

  36. I would add to that list for schizophrenia risk factors – prenatal infection. In pubmed there are numerous papers regarding this. Here is one.
    Prenatal infection and schizophrenia: a review of epidemiologic and translational studies.

    “In this review, the authors discuss and critically evaluate the epidemiologic literature on in utero exposure to infection and schizophrenia, summarize emerging animal models of maternal immune activation, and discuss putative unique and common mechanisms by which in utero exposure to infection alters neurodevelopment, potentially increasing susceptibility to schizophrenia. schizophrenia is illustrated by examples of interaction between in utero exposure to infection and genetic variants.”

    Regarding your list. The two items that I might possiblly (note the double qualifier) view as less promising are the

    “- Social adversity, stressful life events, episodes of maltreatment.
    – Smoking dope. ”

    Because of the tendency for schizophrenia to run in families (along with I believe other disorders such as alchoholism, bi-polar, etc) I might suggest that social adversity and stressful life events may be a by-product of a family struggling with a heavy mental illness burden. But, I’m not committing on that, just a thought.

    Smoking dope. I think the traditionally believed onset of symptoms for schizophrenia is 18-30, but there is some thought that some milder symptoms might appear earlier in the teen years. Self medicating is a common problem with schizophrenia, so smoking dope could be a symptom of earlier onset rather than a trigger. Also not committed, though.

    Just speculating on both of these. I had not heard of the other risk factor, the winter, spring birth. I haven’t done much reading on schizophrenia in the last twenty-some years, since my brother was diagnosed in the eighties.

  37. Smoking dope – Schizophrenics consume stuff. Hanging out with drug users is a good way to blend in when your brain is getting weird on you. Heavy tobacco use is classic. But they consume all kinds of stuff. I know one guy who snorted orange peel. It’s not particularly surprising that if you smoke dope – especially if you smoke a lot of it – you are more likely to receive a schizophrenia diagnosis at some point than someone who doesn’t.

    It’s very hard to sort out the cause/effect/common cause relationships, but when my brother was diagnosed with schizophrenia in 2005 my cursory research suggested there was support for a causative link. “My personal experience” certainly supports a causative link, though we all know how valid that is.

    Trying to get psychiatric care for my brother was complicated by his drug use in a way that suggested that psychiatrists thought there was a link. The first few times we got him to emergency – once we got a judge to allow us to get an ambulance team to kidnap him from the homeless shelter he was staying at – he was denied treatment for schizophrenia because he smoked dope. He was belligerent and knocked out with Haldol as soon as he hit the ED. The next morning the psychiatrist, who had never seen him conscious but could see that he was Black, discharged him on the grounds that he was just stoned. While my brother was still sleeping. And even though a judge had ordered a 3-day observation. Another time my parents were told that he couldn’t be treated for schizophrenia until he completed a detox program. However there was no way he could be accepted into detox program as long as he was prowling around, shouting unintelligibly at both visible and invisible people, and leaving notes about the apocalypse. (He was in the mental health wing of the homeless shelter and the staff and residents there were afraid of him. And really, how much cannabis can someone with no income and limited ability to engage with reality actually procure?)

    Basically, psychiatrists behaved as though there was no way to distinguish between schizophrenia and cannabis intoxication and that therefore there was no point in trying to treat either one. And everyone involved in his care these days is very clear with him that he can’t smoke dope and stay sane. Which is consistent with findings that dope-smokers get their first psychotic episodes younger than non-dope-smokers.

    None of this is clearly causative. My understanding of the literature (which I haven’t looked at in five years) is that triangulating the evidence tentatively suggests it is.

    Still, it’s a risk factor.

    micheleinmichigan, sorry about your brother.

  38. Alison – Thank-you. I’m sorry about your brother as well. It is a bad disease.

    My brother’s drug use was so varied that it would have been hard to make any connection to a particular drug.

    I don’t believe that his psychiatric providers ever withheld treatment based on drug-use. That sounds pretty screwed up. I have heard that PCP use can look like schizophrenia, sometimes but that it wears off in a day or so. So if the patient is held for a couple of days you can tell the difference.

    The main problem seemed to be with my brother’s care is that they would just get him stabilized on a medication, then discharge him. He would almost immediately go off the medication (because it made him feel awful) and be right back to square one with the intense paranoia, etc.

    One a doctor refused to believe that he was mentally ill because he was too clean. Once one put him on MAOI and discharged him with no consideration for that fact that he was living on the streets (got expelled from the residental housing he had for violence) and really doesn’t have the cognitive clarity to follow a strict diet. So he almost died that time. So I can’t say his care has been great. But I hadn’t heard of a no pot requirement.

  39. micheleinmichigan on doctors who don’t know their patients:
    “One a doctor refused to believe that he was mentally ill because he was too clean.”

    Yep, we got that one too. Once he was finally being treated in hospital – where he stayed until he got a discharge plan, which meant finding him somewhere to live that he and his social worker could agree on – his psychiatrist told my mother that one of the problems getting him into treatmentc was he was too well brought up. He knew how to behave appropriately when his freedom was at stake, and did so.

  40. daedalus2u says:

    I think it is pretty well established that autism is a state of increased oxidative stress. That said, the biomedical approach of treating a state of oxidative stress with diet, supplements and antioxidants will not work. A lot of the data supporting a state of increased oxidative stress in autism was done to try and support the false “mercury causes autism” idea. The data showing markers of oxidative stress isn’t necessarily bogus even if the premises and hypotheses used to justify the experiments are bogus. The urinary porphyrin profile used (disingenuously) to try and support mercury exposure is also produced by oxidative stress. The urinary porphyrin profile can’t be due to mercury or lead because analysis shows that there is no mercury or lead present. The porphyrin profile is a sign of an ongoing state of oxidative stress. I appreciate that those results were cherry picked and latched on to scam parents into chelating their children, but that quacks misused the data to scam doesn’t mean the data is wrong.

    All the large well done diet trials (double blind, placebo controlled) show no effect from supplementary antioxidants on any diseases associated with oxidative stress. This is not surprising. Cells learned to control their state of oxidative stress 2+ billion years ago. The reason that antioxidants will not work is because the physiological state of oxidative stress is too important to be set by random dietary quantities of dietary antioxidants.

    Any type of metabolic stress does cause oxidative stress because oxidative stress is the generic stress response mechanism. I think that is the final common pathway by which CNVs are associated with autism. CNVs cause metabolic stress because physiology doesn’t work as well when there are some holes in it. There is a lot of redundancy, and physiology is extremely robust and can compensate for some degree of damage and missing proteins, enzymes or what ever those missing or extra genes produced. Inducing a state of oxidative stress is one of the ways that physiology does compensate for everything not being exactly right.

    One of the ASDs, Rett Syndrome is known to be caused by a single deletion of the MeCP2 gene. That codes for a protein that binds to methylated DNA and so helps to regulate the readout of epigenetically programmed DNA. MeCP2 is on the X chromosome, deletion in males is lethal. Females have 2 X chromosomes, one is deactivated at random. The presence of some cell with appropriate MeCP2 readout of epigenetically programmed DNA “rescues” the phenotype and so females with the deletion survive, they just have Rett Syndrome.

    I think it is the metabolic stress of not having all the cells working together “in sync” that produces the RS phenotype. In the mouse model, turning off the MeCP2 gene produces symptoms that recapitulate the symptoms of human RS extremely well. Turning the MeCP2 gene back on makes those symptoms go away.

    People with RS don’t have “classic” autism symptoms, it is “autism-like”. I think that is because the symptoms of RS only start at age 6-18 months. I think that because they didn’t have the exposure to what ever “causes” the autism in utero (my hypothesis is low NO), they don’t have the autism neuroanatomy that develops in utero. This tells me there are at least two components to autism, the neuroanatomy which happens in utero, and the ongoing stuff which maintains the autism phenotype after someone is born.

    Oxidative stress does lower NO levels. Many of the signal pathways that are triggered by oxidative stress are triggered by low NO and not necessarily by high levels of ROS. Low NO and high ROS always go together. You can’t have high NO and high ROS. The only time you can have low NO and low ROS is in utero, when the O2 partial pressure is low. At every other time, a low NO state will always cause high ROS because of the presence of O2.

  41. passionlessDrone says:

    Hi Deadulus2u –

    All the large well done diet trials (double blind, placebo controlled) show no effect from supplementary antioxidants on any diseases associated with oxidative stress.

    I’m wondering if you would comment on the seemingly large number of studies on Pycnogenol in this regard. I’m starting to learn that not all studies are well done, but there do seem to quite a few people looking into this particular compound for a variety of anti-inflammatory uses, and some of the studies below indicate reductions in oxidative stress markers, though I’m not positive this correlates directly to ‘any diseases associated with oxidative stress’ or not. (?)

    A couple I found:

    There are a ton more, this compound looks to be getting a lot of attention. Anyways, I would be interested in your thoughts.

    – pD

  42. daedalus2u says:

    pd, 3 months is short term. These are all small trials. The trials that have shown no effect of nutritive levels of antioxidants were over 100 times larger and multi-year trials. Polyphenolics are most likely not absorbed into the blood stream very much, so via what mechanism there is a therapeutic effect is not at all clear.

  43. Werdna says:

    Those studies by the numbers:


    ?/? (Not in abstract and I don’t have a subscription to that)

    My only comment is that those are on the smallish side. Only the final one talks about autism and it’s not clear (from the abstract) what is meant by “improvement” so it’s difficult to judge if the n is sufficient to warrant much excitement.

  44. daedalus2u says:

    A systematic review and meta analysis of this is here (open access)

  45. Werdna says:

    That’s interesting. A little weird about treating diseases collectively – I keep thinking that you are only going to see an effect that’s severe – but on the other hand I like that it has a hard endpoint. A great cautionary tail that the RR’s are elevated for most of them except for C and Selenium which aren’t significant.

  46. daedalus2u says:

    I think the elevated RRs are real. What I don’t like about the article is that they suggest a non-physiological difference between antioxidant nutrients from food and from supplements. There is no difference between nutrients from food and from supplements. If supplemental nutrients from supplements don’t improve health, then neither should supplemental nutrients from food.

    The problem is reconciling this with the very robust data that good health is associated with a diet rich in “healthy foods”. If nutrients in those healthy foods are not responsible for the good health, then what is the explanation for the correlation?

    I think the reason is that the diet studies are all self-selected. My hypothesis is that because free radicals are very reactive, they are ideal signaling molecules. There is a low background, and they react very rapidly. There are many signaling pathways that use free radicals. You can’t just hammer away at free radicals and flood the body with antioxidants and expect there to be no physiological response. Signaling with free radicals implies an appropriate background of antioxidants, not too low, and not too high. Physiology has unlimited capacity to destroy antioxidants by simply making more superoxide. I think that is what physiology does when excess antioxidants are consumed, and that is what accounts for the slightly increased RR.

    When your body’s oxidative setpoint is high, physiology compels you to choose a diet devoid of antioxidants to spare the body the physiological need to destroy those antioxidants at some metabolic cost. Only when the oxidative setpoint is low is there there choice of foods high in antioxidants. The association between diet and health is because people who are healthy choose a good diet and people who are unhealthy choose a crappy diet.

  47. daedalus2u says:

    As a meta comment, the hypothesis I laid out in the above comment, that bad health causes a bad diet is an example of an alternative hypothesis which should have a high a priori prior plausibility because it is compatible with more of the data than the other ideas that attempt to explain the data.

    It is completely compatible with all of the data that was used to develop the “bad diet causes bad health” idea, but it is not compatible with the idea that the causal chain runs from bad diet to bad health (I find myself reluctant to use the term hypothesis when there is a better explanation that fits all the data a particular idea does but also fits a lot more data. I consider it to be cherry picking to pick an idea that fits less of the data when there is an alternative idea that explains more (the idea that explains the most data is the one that I apply the term hypothesis).

    It should have a higher plausibility than the bad diet causes bad health idea, because in addition it also explains all of the large long term supplement studies which show the opposite of what the bad diet causes bad health idea predicts.

    Why it is considered to be implausible is about human nature and the resistance of many to abandon explanations that are generally accepted. It forces people to accept that maybe their health is less under their control than they would like to think and that people who are unhealthy may not have brought it on themselves. Being in a state of bad health may not be the karmic justice from eating a bad diet. That compels greater compassion for those in ill health (in those capable of greater compassion) and a search for other explanations and perhaps other interventions.

  48. Jean Mercer says:

    In addition to the above, people who choose poor diets may do so because of additional factors such as poverty that contribute both to poor health and to the availability of appropriate foods or to preferences due to the familiarity of inappropriate foods. Once you get into the use of self-selected groups, the door is open to a myriad of confounding variables and confused causes and effects.

    I might also point out that studies of this type are dependent on self-report of diet and often of health conditions, and self-report is in turn affected by the beliefs and expectations of the participants. In the case of autistic children, reports of parents who chose to give the children supplements are likely to be influenced by the belief system that led to the choice of treatment. There’s even a potential effect due to behavioral changes in parents who feel they’ve found a solution to all their troubles.

  49. daedalus2u says:

    Jean, the supplement studies I was talking about were large (many thousands), double blind and placebo controlled. Those who determined the clinical endpoints were blinded to the supplement status of those they were evaluating.

    I am unaware of any blinded diet studies. Diet is extremely difficult to manipulate experimentally except in patient. People simply don’t follow the directions, they eat what they want to eat.

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