August 29, 2012

Autism does not have genetic causes

Not a single SNP was found to influence the development of autism spectrum disorders in an ample GWAS study:

Richard Anney et al., Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Human Molecular Genetics 2012. Open access ··> LINK [doi: 10.1093/hmg/dds301]


While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

A synthetic report on this paper may be found at The Spitoon.

This study seems to effectively discard any major genetic influence in autism and forces us to look again for environmental clues like environmental pollutants, pregnancy conditions, early parental care (such as breastfeeding), vaccines, etc. in order to understand the causes behind these problems. Per Wikipedia:

Environmental factors that have been claimed to contribute to autism or exacerbate its symptoms, or may be important to consider in future research, include certain foods, infectious disease, heavy metals, solvents, diesel exhaust, PCBs, phthalates and phenols used in plastic products, pesticides, brominated flame retardants, alcohol, smoking, illicit drugs, and vaccines.

Common pollutants, notably many common plastics, pesticides, etc., are high among the likely causes of the disorders, as well as many other modern diseases.


  1. It's not that there isn't a genetic cause underlying the condition, it's just that no individual SNP shows itself as being a significant contributing factor.

    That's why he said they exert weak effects.

    I wonder what twin studies have shown.

    1. They don't seem to be the causes, although they may act as protective or facilitating elements. Without clear genetic causes, we must conclude it is environmental - of course as lung cancer, genetic factors will also be at play to some extent, but seldom as causes.

    2. Exactly, the statement that "This study seems to effectively discard any major genetic influence in autism" is directly contradicted by the abstract itself which says "it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs)."

      ASD are Anna Karenina disorders. People without ASDs are all the same; people with ASDs are all dysfunctional in their own unique way. A parent who has an ASD is extremely likely to pass it on to a child. But a parent without an ASD may very well have one child who has an ASD and another who does not. But, most cases of ASD are attributable to novel mutations relevant to one or more of a large coordinated complex of genes in that particular child. There is also some indication that the total mutational load is relevant (i.e. you need on average X mutations in the relevant complex of genes for that entire system to partially fail in a way that produces an ASD), by looking at patterns of heredity that incorporate sub-clinical ASD symptoms.

      This model is supported by the strong association of ASD rates with advanced paternal age which is strongly corrolated with rates of novel mutations in sperm cells. Also, to the extent that parental environmental exposure has been empirically linked to ASD, which a couple of studies have suggested, it is exposures of the father and not that mother that have been implicated, again suggesting an impact mechanism of increased rates of novel mutations in the father's sperm. The fact that ASD almost always manifest a very young age, likewise disfavors the kind of genetic succeptibility to environmental impacts model that we see, e.g., in PTSD.

      The paper cited in the original post doesn't dispute this analysis. It simply makes the point that ASD does not fit a Mendelin genetic model such as one where the same common genetic variant which may be dominant, recessive, X-linked recessive, or whatever causes the disease.

      ASD symptoms are not specific to the specific mutations in the complex of relevant genes that cause the syndrome. ASDs are the fevers of genetic mental health problems. One might liken the effect caused by particular mutated genes to the cumulative effect of having insufficient lubrication on too many parts of a complex set of gears in an old fashioned clock or engine to the point where it starts to gum up the work. It doesn't really matter which particular piece in the total mechanism is gummed up - the effect is the same.

      Contrary to the claim of princenuadha, the case that there is any meaningful nuture element to ASD has not been made despite many attempts to do so, with few of the failed attempts being published. For example, the purported link to vaccination has been definitively ruled out, efforts to link ASD to diet have not held up to scrutiny, and neither have efforts to link ASD to parenting style.

      Despite the lack of any particular common genetic variant as a cause, the balance of the evidence show that the predominant cause of ASDs is rare genetic variants.

    3. Some of the blog posts I have done of the evidence for a genetic cause of ASD together with a toy model of the inheritance patterns can be found here. The toy model is based mostly on this PNAS paper. As a now paywall blocked report that I had quoted explained: "Studies of identical twins show that when one twin has autism, about 90 percent of the time the other twin will too. . . . people with autism had the same number of deletions [ed. i.e. places where DNA is usually present] as people in a healthy control group did. However, people with autism tend to have deletions that remove parts or all of genes, while healthy people carry deletions on stretches of DNA that don’t contain genes. 'You and I may have just as many deletions in our genomes, but since they don’t hit genes, we don’t have autism. . . . This is a natural part of being a human being. We get mutations. Most of the time it’s not a problem, but sometimes it hits a gene involved in autism.' . . .Many of the people with autism had more than one spot in the genome where they were missing large chunks of DNA, each about 30,000 base pairs long. . . . Each of the specific variants was rare on its own, with even the most common found in less than 1 percent of people in the study. . . . 'Most individuals with autism are genetically unique,' . . . Although each person with autism appears to have a distinct set of genetic variations, the genes affected by the variants tend to affect similar biological processes."

      There are candidates for the X-linked protective gene: "One gene strongly linked to autism in the new study is called DDX53-PTCHD1, and is located on the X chromosome," and "[M]utations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR."

      Re Subclinical effects see: J.N. Constantino et al. Sibling recurrence and the genetic epidemiology of autism. American Journal of Psychiatry, in press, 2010. doi:10.1176/appi.ajp.2010.09101470 and Campbell BC, Wang SS-H "Familial Linkage between Neuropsychiatric Disorders and Intellectual Interests." (2012) PLoS ONE 7(1): e30405. doi:10.1371/journal.pone.0030405

      "[A] child born to parents who already have one child with an autism spectrum disorder has approximately a 4 to 10 percent chance of also developing one of these disorders, including Asperger syndrome. In families without a history of autism spectrum disorders, the chance of having a child with one of these disorders is approximately 0.7 percent."

    4. Andrew: you may have a point re. unique mutations (although it's strange that all produce similar syndromes) but twin studies alone are not enough because twins have the same environment in the womb and, usually, also after birth, so you cannot discern between genetic and environmental causes so easily, specially if they add up.

      In any case the study, signed by dozens of experts, seems very conclusive in stating that common genetic variants are essentially irrelevant in autism. This is important for example when we speculate on Neanderthals and autism or rock art and autism, etc. (we can discard all that). And also for more practical reasons of present day.

      I feel tremendously skeptical anyhow about blaming most of such a common disorder as is autism senso lato (ASD) to just "rare variants". Maybe you are right but I feel that in most cases it must be a common cause or a limited array of causes, like exposure to common pollutants, which we know are troublesome also in other aspects.

  2. And just to add, i understand that autism is very much a "nurture" issue also.

  3. From this Sundays NYTimes
    Immune disorder at the root of autism

    1. A couple of points on the NYT opinion piece (which I blogged at greater length at the blog where I discuss mental health and political issues (as opposed to physics and anthropology):

      * The author claims that up to 1/3 of autism cases may have an auto-immune component, some genetic in source and some related to exposures to maternal immune responses in the first two trimesters of pregnancy. Maju's point on identical twins sharing both a prenatal environment and genes is well taken in this regard.

      * The opinion piece is consistent with the emerging evidence that ASDs are overwhelmingly congentital (i.e. present at birth). Environmental effects after birth may have some minor impact on severity of symptoms but not presence or absence of the condition.

      * Under standing the mechanism by which autism symptoms are caused in at least an important subset of cases is valuable is suggesting new therapies to manage or treat ASD symptoms. Suppressing immune responses during pregnancy and suppressing inflamation during key developmental period of the brains of children with ASD, or some sort of therapy to reset the epigenetic data imprinted during prengancy on the child would be the most promising routes for treatment. This is all pie in the sky stuff, however.

      But, rather disappointingly, if autoimmune driven inflamation is the main mechanism that drives the symptoms, a lot of the time consuming and heartfelt efforts that families of ASD children engage in with the hope that it may have theraputic effect may be futile. On the other hand, knowing the causes can help relieve families and teachers of a lot of misplaced guilt.

      * "I feel tremendously skeptical anyhow about blaming most of such a common disorder as is autism senso lato (ASD) to just "rare variants". Maybe you are right but I feel that in most cases it must be a common cause or a limited array of causes, like exposure to common pollutants, which we know are troublesome also in other aspects."

      The NYT article author blames the hygenic effect, and others can rightly point to rising average parental age. But, keep in mind that a very large share of the rise in autism rates has been offset by a decline in developmental disabilities not elsewhere classified. This is an old issue with a new name for the most part and not nearly as rapidly a growing "epidemic" as diagnosis rates would suggest.

      Psychosis (i.e. schizophrenia and bipolar disorder) follow a lot of the same inheritance patterns and causation structure as ADSs. One way to conceptualize it is that there is one underlying condition - "disorders caused by non-fatal background mutational noise" whose symptoms vary based on which particular places the mutations (not only new SNPs, but deletions and copy number variations) crop up. If the mutations impact genes that aren't activitated, there is no visible symptom. If the mutations impact are pretty simple biological system, then all mutations hitting that small genetic target looks like a Mendelin disease (and may become one) and gets separately classified. But, when a whole lot of genes need to work together in one tightly bound system, something that more often happens for mental health conditions than physical health conditions that don't lead to spontaneous abortion, three of the most common systems to be disrupted, presumably because they are the largest and most complex ones, give rise to ASDs or schizophrenia or bipolar disoder. ASD impacts a brain system that needs to work right away so it manifests early, while schizophrenia and bipolar disorder impacts brain systems that are redundant until the brain streamlines its connections in adolescence and young adulthood, so they manifest later.

  4. @Aeolius,

    Thanks - very informative article!

  5. What about Fragile X syndrome?
    The autism in children who had fetal rubella sydrome suggests toxin or viruses could cause many cases.

    The main problem is that austism is that it is a syndrome (a pattern of symptoms) but that does not mean it has a single cause for all cases.
    A child who in 1960 (when I started medical school) would have been called mentally retarded and/or childhood schizophrenic (and probably institutionalized) is now sitting at home.
    And then we have all the geeky kids added to the autism spectrum.
    Prince Nuadha's comment is even more out of date: The "frigid mothering" as the cause of Autism was first posited in the late 1930's, and pushed by Bettelheim, but no one believes it anymore.
    However, it makes one wonder if a mother with mild Asberger syndrome would give birth to a child with the full spectrum..

  6. How does it fit with this study?

    1. It does not seem to "fit" directly but I don't think they are incompatible either: one is about symptoms and another about causes.


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