UCLA’s David Geffen School of Medicine and Semel Institute for Neuroscience and Human Behavior have released a paper that
demonstrate[s] a relationship between frontal lobar connectivity and common genetic variants in CNTNAP2. These data provide a mechanistic link between specific genetic risk for neurodevelopmental disorders and empirical data implicating dysfunction of long-range connections within the frontal lobe in autism. The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such as autism in part through modulation of frontal lobe connectivity.
“This is a key piece of the puzzle we’ve been searching for,” said co-principal investigator Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics. “Now we can begin to unravel the mystery of how genes rearrange the brain’s circuitry, not only in autism but in many related neurological disorders.”
For anyone genuinely interested in the science behind autism this is fascinating and exciting news. For the very first time science illustrates how a gene variant tied to autism rewires the brain. For those merely interested in continuing to support the idea of an epidemic to uphold their own unscientific but heavily personally invested causation ideas this news will hopefully be a wake up call.
Over at autism.about.com, Lisa Jo asks
For many parents, of course, the $64,000 question is not “what do autistic symptoms look like,” but rather “what causes these symptoms in the first place?” If the problems are a result of spontaneous genetic mutations, what causes those mutations to occur?
I would respectfully say to Lisa Jo that answering the question of what causes specific genetic mutations was beyond the scope of this particular paper but that _without_ this paper it would’ve been impossible to say with any accuracy how exactly the gene in question affected development. Without that knowledge, looking for answers to causation would be very difficult.
Left Brain Right Brain 
It’s important to note that the CNTNAP2 genetic variation is carried by 1/3 of the entire general population as noted by the authors of the study:
“The authors emphasized that the patterns of connectivity found in the study still fall along the spectrum of normal gene variation. “One third of the population carries this variant in its DNA,” noted Geschwind. “It’s important to remember that the gene variant alone doesn’t cause autism, it just increases risk.”
Common genetic variants have been implicated in autism, the first was the association between the serotonin transporter genetic variant which is present in over half the general population.
Hakonarnson reported that children with ASDs were more likely than healthy controls to have gene variants on a particular region of chromosome 5. That region is located between two genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal cell-adhesion molecules.
Hakonarnson also claimed that if this mutation could be eliminated 15% of autism cases would disappear. What he did not report in his round of media blitzes is that this common genetic variant is present in 60% of the general population and that every one of the media interviewers he made this claim to have a better than 50/50 chance of possessing this ‘autism’ genetic mutation.
These types of studies always carry the catchy media headlines that appear almost monthly of ‘New Autism Gene Identified!’ The risk carried by common genetic variations is so tiny that the claims by the molecular geneticists always outweigh the evidence
Kev – I don’t disagree with you, and in fact I think you’re quite right that this is a remarkable achievement irrespective of its relationship to autism.
Nevertheless, my readership consists largely of parents. And I think I’m correct in saying that most parents aren’t so much interested in a “remarkable achievement” as they are in either understanding the source of their child’s autism or in preventing autism in a yet-to-be-born child.
Very often, “breakthroughs” in autism aren’t really breakthroughs in autism at all, but rather breakthroughs in tangentially-related areas of genetics, imaging, neurology, and so forth. Of course, it’s always great to have a breakthrough, but I am not so keen on the publicists hitching their stars to autism in order to get media attention!
Lisa
Lisa;
This is no breakthrough at all. The CNTNAP2 variant has also been implicated in schizophrenia, intellectual disability with or without co-occuring autism, learning disorders, ADHD, language disorders, bi-polar disorder, intellectual disability with seizures, in fact, just about every nuerodevelopmental and psychiatric disorder has implicated the CNTNAP2 common genetic variant present in 1/3 of the general population.
The question these association raise but never answer is ‘why are the parents unaffected’? There is a design problem in the strategy in autism genome studies of recruiting multiple incidence families (AGRE, IMGSAC in Europe) and single incidence collections such as the Simmons Foundation samples.
What you think you are observing is an ‘autism’ susceptability gene but what is never recognized is that these associations are not specific to autism. The geneticists may have to think in a different sort of way and realize that there are no diagnosis-specific susceptability genes. These gene associations may have to be thought of as representing candidate genes for neurodevelopmental alteration risk with other environmental and genetic influences involved in the transition to a broad spectrum of neurodevelopmental and neuropsychiatric conditions.
And again, why are the parents unaffected? Sir Michael Rutter is now questioning the value of gene-hunting and has also observed that the behavioral geneticists consider the environment as a ‘nuisance’ to be ignored.
Kev – the achievement I’m referring is not related to the genetics per se but to the ability to visualize changes in brain patterns which develop (presumably!) as the result of a particular genetic anomaly. Up until now, we haven’t been able to actually “see” changes in brain patterns.
As regards parents being affected, maybe I’m misunderstanding but it seems to me that (1) a lot of genetic anomalies are spontaneous and not inherited and (2) a lot of parents ARE affected, though they may have fewer anomalies and thus find it a bit easier to compensate.
Lisa
“As regards parents being affected, maybe I’m misunderstanding but it seems to me that (1) a lot of genetic anomalies are spontaneous and not inherited and (2) a lot of parents ARE affected, though they may have fewer anomalies and thus find it a bit easier to compensate”.
There is bit of a a misconception that considers the concepts of ‘genetic’ and ‘inherited’ as being interchangeable. If you look at the genetic syndromes associated with autism, Fragile X stands alone as being primarily ‘inherited’. Downs Syndrome and Rhetts Syndrome are virtually always the consequence of a de novo mutation with a reccurance risk of less than 1%. What may be not realized is that other genetic syndromes associated with autism are nearly always primarily associated with de novo mutations. Two thirds of Tuberous Sclerosis patients have a de novo mutation in either the TSC1 or the TSC2 genes. In Pradi-Willis syndrome 70% of the cases involve a de novo mutation in the same region of chromosome 15 as Angleman’s Syndrome and in Anglemans Syndrome the UBE3A mutation is either de novo or inherited from an unaffected parent.
Recurrance risk is less than 1% in the case of de novo mutations and substantially higher in inherited cases. De novo mutations by definition are not present in the parents and therefore cannot be associated with the genetic influences underlying ‘autistic-like’ traits.
As far as parents being affected I assume you are referring to the broad autism phenotype (BAP). There is a huge difference between common normal trait variations that extends very broadly, not only within the families, but throughout the general population but these ‘traits’ not a handicapping condition. There is a model currently being explored that was introduced by Rutter. This model suggests that the genes underlying the BAP are not the same as the genetic (Downs Syndrome) and environmental (congenital rubella syndrome)factors involved in the transition to the handicapping disorder and that autism etiology involves a multiplicity of genetic and environmental factors associated with risk for neurodevelopmental alterations (primary mechanism) and that the seperate mechanisms underlying the BAP is determinative of a developmental trajectory towards an autism diagnosis but is not an independant etiologic factor.
These studies are now being explored and if proven will mark a profound sea change in understanding the biological complexities of autism etiology away from the concept of autism as a primarily genetic disease.
“As regards parents being affected, maybe I’m misunderstanding but it seems to me that (1) a lot of genetic anomalies are spontaneous and not inherited and (2) a lot of parents ARE affected, though they may have fewer anomalies and thus find it a bit easier to compensate”.
There is bit of a misconception that considers the concepts of ‘genetic’ and ‘inherited’ as being interchangeable. If you look at the genetic syndromes associated with autism, Fragile X stands alone as being primarily ‘inherited’. Downs Syndrome and Rhetts Syndrome are virtually always the consequence of a de novo mutation with a reccurance risk of less than 1%. What may be not realized is that other genetic syndromes associated with autism are nearly always primarily associated with de novo mutations. Two thirds of Tuberous Sclerosis patients have a de novo mutation in either the TSC1 or the TSC2 genes. In Pradi-Willis syndrome 70% of the cases involve a de novo mutation in the same region of chromosome 15 as Angleman’s Syndrome and in Anglemans Syndrome the UBE3A mutation is either de novo or inherited from an unaffected parent.
Recurrance risk is less than 1% in the case of de novo mutations and substantially higher in inherited cases. De novo mutations by definition are not present in the parents and therefore cannot be associated with the genetic influences underlying ‘autistic-like’ traits.
As far as parents being affected I assume you are referring to the broad autism phenotype (BAP). There is a huge difference between common normal trait variations that extends very broadly, not only within the families, but throughout the general population but these ‘traits’ are not a handicapping condition. There is a model currently being explored that was introduced by Rutter. This model suggests that the genes underlying the BAP are not the same as the genetic (Downs Syndrome) and environmental (congenital rubella syndrome)factors involved in the transition to the handicapping disorder and that autism etiology involves a multiplicity of genetic and environmental factors associated with risk for neurodevelopmental alterations (primary mechanism) and that the seperate mechanisms underlying the BAP is a background effect determinative of a developmental trajectory towards an autism diagnosis but is not an independant etiologic factor.
These studies are now being explored and if proven will mark a profound sea change in understanding the biological complexities of autism etiology away from the concept of autism as a primarily genetic disease.
The story above says so little, it is of no value scientifically. I smell a rat. Blaming the victims has been consistently attempted so that the spontaneous genetic mutations caused by vaccine ingredients will be overlooked. Shame on this site for misleading (or trying to) with this speculative nonsense.
Ross Coe,
Someone, I guess, had to pull this back to vaccines. The “blaming the victims” argument is very strange in this case. How exactly is it blaming the victims when one puts forth the idea that genetic differences could be linked to observed physical differences in the brain.
Ross Coe, you do realize that the “spontaneous genetic mutations” you mentioned were generally germ line mutations present in the egg or sperm before fertilization–and thus (think Down syndrome) were generated at least nine months before the child’s first vaccination, don’t you?
‘Autism’ is a bunch of very loosely defined characteristics involving complex behavioural domains. ‘Autism’ is not the underlying factor(s) that cause those characteristics. In some people, the origin of those characteristics might be purely genetic. In others it might be purely environmental. In still others there might be a genetic predisposition interacting with environmental factors.
Linking autism with genetic variations in some people does not preclude environmental causes in others. Genetically determined abnormalities of ‘brain wiring’ in some people with autism does not mean that all people with autism developed abnormal ‘brain wiring’ in utero.
There is widespread agreement amongst researchers that autism (the symptoms) is a heterogeneous condition, but you would never know it to look at the headlines.
Eleanor, to the extent that “autism” has common behavioral patterns, it must have common neuroanatomical causation pathways. Because neuroanatomy changes over time via neurodevelopment, the development of common neuroanatomical pathways are presumably due to common neurodevelopmental pathway(s).
We know there are non-genetic causes of autism, from teratogens (valproate, thalidomide and others), and from exposure to maternal stress in utero.
We know there is genetic linkage because of the high heritability (but this is complex because of the very strong in utero effects (dizygous twins have a higher concordance than full siblings)). A great many single and few gene mutations (deletions and multiplications) have been found that seem to be causal. Rett Syndrome has genetic causation and is an ASD.
Presumably there are common pathway(s) that links genetic causes and environmental causes to the common neuroanatomical pathways that produce the common behavioral patterns.
It is my opinion that the “widespread agreement among researchers that autism (the symptoms) is a heterogeneous conditions)” is limited to those researchers doing genetic research because they can’t find commonalities in the genes but they know autism is a genetic condition because “the genes” do “everything”.
Researchers doing genetics are not looking at the environment at all, so they have no idea what a gene-environment interaction would even look like.
Daedalus – I don’t see that similar symptoms absolutely mean similar causes. As an example, headaches can be caused by neurological issues, but also by a blow to the head, stress, or even a hangover. Seizures can have many etiologies as well.
When a person has perseverative or non-communicative behavior, the reasons can be just as diverse.
Lisa
Hi Daedalus
The taxonomy of ‘mental’ disorders used by psychiatry is based on symptoms because from the time the taxonomy was devised until now, we generally haven’t had reliable knowledge about the causal pathways involved in said disorders.
Kanner felt that ‘disturbances of affective contact’ in children were noteworthy, because at the time the psychodynamic model dominated psychiatry and social interaction was seen as foundational to human behaviour, not as just one facet of it.
Although there is no doubt that some people meet the diagnostic criteria for autism, all that really tells you is that they meet the diagnostic criteria for autism. Meeting those criteria suggests that the frontal lobes and temporal areas are probably involved, but it tells you nothing about causation, nor which neural pathways are affected or how.
Social interaction, communication and stereotypical behaviours are each highly complex behavioural categories. If you were to list all the brain areas involved in social interaction during the first five years of a typically developing child’s life, you would end up listing more or less all of them. That doesn’t mean that people with autism necessarily have pervasive abnormalities of brain development, what it means is that there is an impairment in one or more of the many component factors that are co-opted in the development of typical social interaction. Similarly for communication skills. And adaptive behaviour. But different component factors could be affected in different people, and all of them could still end up with (different) impairments in social interaction, communication and with stereotypical behaviour.
If all people diagnosed with autism had closely matching characteristics, then I agree, you could say they must have common neuroanatomical causation pathways. But they don’t. Nor are their ‘impairments’ limited to the three key areas of the diagnostic criteria. The diagnostic criteria are useful in distinguishing people with autism from, say, people with showing the characteristics we call schizophrenia, but it doesn’t mean all people diagnosed with autism have the same underlying cause for their characteristics.
I don’t get the impression that the view that autism is a heterogeneous condition is limited to geneticists. ‘Time to give up on a single explanation for autism’ by Happe, Ronald and Plomin is one paper that springs to mind
http://www.nature.com/neuro/journal/v9/n10/abs/nn1770.html
and the heterogeneous nature of autism is something that is now almost always mentioned side-by-side with the diagnostic criteria in the opening paragraphs of research papers.
What tends to happen in research designs, by contrast, is that all members of experimental groups are treated as if they all have the same condition, because we still haven’t identified the biological markers for sub-groups.
Lisa gives some good examples of symptoms with diverse etiologies. Co-occurring sore throat, headache and skin rash is another. To be sure, the throat, head and skin are involved regardless of the cause, but the underlying causes can vary considerably.
The revisions proposed in the DSM V remove the previous subdivisions; Asperger’s, autism, CDD, PDD NOS and replace it with a single diagnosis, autistic disorder.
http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=94#
I agree that there can be multiple causes for the same symptoms, but there can also be a single common cause for the same symptoms and a single cause for multiple symptoms. Until the “causes” are known and understood how they map onto the symptoms, it is premature to say if there is one cause or many causes.
The major rationale given in the paper cited (time to give up…) is genetics. That paper has a naïve (and wrong) concept of how genes are connected to behaviors. Genes do not code for “behaviors” or “traits”, unless those “traits” are the product of a single gene, such as eye color. Behaviors are only products of a brain that has gone through neurodevelopment. No behavior is a product of a genotype, behaviors are only products of a phenotype; emergent properties of a phenotype that has gone through neurodevelopment.
I appreciate that gene researchers want to look at behavioral “traits” as if they are due to linear combinations of genes. Unfortunately this approach will fail because the emergent properties of phenotypes are not linear functions of genes. Nothing about physiology is linear except in small, narrow non-physiological ranges. Behaviors are among the most non-linear of physiological characteristics.
Their characterization of “environment” as only the environment after a child is born is breathtakingly naïve. Monozygous twins share an in utero environment where they grow from a single cell to 10^12 cells. Presumably that shared environment may (must?) have effects that are shared in addition to the shared genome? Presumably that shared environment may be even more important than the postnatal environment where they only grow by a factor of 10 in size and the brain doesn’t grow anywhere close to that much?
It is well known that the concordance of autism in fraternal twins is much higher than in full siblings. That increased concordance is due to the shared in utero environment. Presumably some of the concordance in monozygous twins is due to their shared environment and not just to their shared genome.
I appreciate that gene researchers want to ignore the environment (in utero and postnatal) because they have no ability to measure or control for it. There isn’t much I can say to them except welcome to the real world, and stop looking for the answer only where it is easy to look.
Sorry to sound harsh, but gene researchers have been hyping their work in autism for many years and there is still essentially nothing to show for it.
I was at an autism conference and was talking with a gene researcher, and he was poo-pooing my n=1 data (but on multiple instances) as an “anecdote”.
I told him that all he had was anecdotes too because each of his subjects was unique too, and that there wasn’t enough matter in the Universe for there to be enough subjects for him to get “good” statistics on the effects of different genes.
He didn’t respond because he knew I was right. Once you start looking at multiple gene interactions, the number of permutations becomes so large that you simply can’t access the parameter space experimentally.
Once you go beyond the cases where single or few gene deletions or duplications lead to an autism (or autism-like) phenotype, the genetics become impenetrable with no gene contributing more than a few percent to autism incidence. If no gene contributes more than a few percent, that implies (at least) 25 or 50 genes. 25 factorial (25!) is ~10^25. 50! is 10^64. The number of stars in the Universe is only ~10^22. The number of humans that have ever lived is only something like 10^11.
DSM: The taxonomy of symptoms presented in the various editions of the DSM is often singularly unhelpful, and the subject of considerable controversy. Over the years, co-occurring symptoms have become reified into ‘conditions’ when there is often little evidence that there is a single ‘condition’ underpinning the symptoms at all. ‘Depression’ and ‘anxiety’ are good examples. Umpteen different things cause depression and anxiety. But people still come out of their doctor’s surgeries with a ‘diagnosis’ of one or the other.
Multiple/single causes: I totally agree. However, in research designs, there is often an implicit assumption that there is a unitary cause. A not uncommon pattern is as follows. Three (hypothetical) studies on, say, pitch perception in autistic people are undertaken, each by a different research group. Each of the studies uses a slightly different (but not complementary) methodology, so together the results are inconclusive. One study has ten participants and finds significant differences between the autistic group and controls. The second study has 20 participants and finds no significant differences. The third study has 18 participants and finds that one autistic person has such different reponses from the rest of the experimental group that his results are treated as an ‘outlier’ and discarded. The selection of autistic participants on the basis of the DSM diagnostic criteria, the pooling of group results, and the small numbers of participants involved, implicitly assumes that all autistic participants have the same characteristics and the same underlying cause for them. What then happens is that it is concluded that pitch perception is not a distinguishing characteristic of ‘autism’ and the research is not followed up.
“Time to give up…” paper: I cited this simply as an example of researchers who are not geneticists proposing that autism be construed as a condition with a heterogeneous aetiology. Personally I think the starting point of their analysis – ‘fractionation’ of the diagnostic criteria for autism – is misplaced, but since they were based at the Institute of Pyschiatry when they wrote it, I can understand why they took this approach. But I can’t see any indication of them claiming that genes ‘code for’ behaviours or traits. They consistently use the term ‘contribute to’. I don’t disagree with your arguments about non-linearity at all. But I suspect you are attributing to the authors of the paper a view they don’t hold. [Incidentally, are you sure eye colour is the product of a single gene?]
You are right, eye color is a bad example because it is polygenetic. Blood type is a better example.
“Linking autism with genetic variations in some people does not preclude environmental causes in others”.
Nor does it preclude genetic variations not being involved in environmental cause. What do genetic variations actually do to cause ‘autism. Much media excitement was generated over the idea that copy numer variations ’cause’ autism. Copy number variations by themselves may do nothing, but it is the environment acting upon copy number variations that can also cause disease. Aids researchers have found that lower copy number variations in a single gene, CCL3L1 located in the region of chromosome 17Q11.2 substantially increases the risk for infection after exposure to HIV.
http://www.ncbi.nlm.nih.gov/pubmed/19287150
No one is the AIDS research community is stating that a ‘New AIDS gene has been discovered!’ but that is exactly what the autism genecists claim.
Wow RAJ,
Citing genetic research from AIDS work is certainly a strange way of trying to undermine autism genetics. Is there not reason for the media to be excited that science has pinpointed an area ripe for further investigation? It’s much easier to study disease mechanisms once you’ve identified a source.
What that means is that you might not be able to build a perfect classifier, but it doesn’t preclude a good classifier.
Let me give an example. A screening tool like the AQ test has 50 questions. Let’s say there are 4 answers for each question, so the total number of permutations is 4^50. Yet, you can build a pretty good classifier that takes into consideration all 50 questions, with data from only 1000s of tests.
While I’m not sure that RAJ’s HIV-related example is the best choice, it is useful to consider ASD genetics in context.
A better example might be human adult stature, a classic polygenic trait which, like ASD, has long been considered to be highly heritable (ca. 80-90%). Tall people tend to have kids who grow to be tall, short people tend to produce short offspring. Sir Francis Galton showed in 1886 that “when dealing with the transmission of stature from parents to children, the average height of the two parents, … is all we need care to know about them.” While Galton’s idea has been considerably refined, and there are clear environmental influences, it still seems that the variation of height within a population is to a large extent genetically determined.
So, where’s the “height” gene?
The first genes associated with human adult stature were reported only a few years ago. By the time we reached about 50 associated genes, the variability in adult height ascribed to variations in those genes was—wait for it—a few per cent. We’re now at about 600 height-associated genes and climbing—and these variants together still explain only a small fraction of the variation.
Accordingly, just as with ASD, you could argue that genetics is not a major contributor—but of course you’d still have to explain why tall people tend to produce tall offspring, etc. It might be useful to look at it a little differently:
Joseph, yes. But in your example the 50 questions are all independent and don’t interact. They certainly don’t interact non-linearly.
The test is also designed and modified until it does give results that are interpretable. It was designed for ease of interpretability. Genomes were not designed, and were certainly not designed to be modular, separable, or interpretable.
Brian, the problem with that example is that there has been a secular change in the average height.
Click to access baten_global.pdf
If you look at figure 2, there are some pretty large changes in the average height over times that are very short in an evolutionary sense. Those changes can’t be genetic. If parents are tall, and they pass on to their children what ever environmental influence it was that made them tall (better nutrition perhaps), the “tall parents = tall children” correlation doesn’t need to have genetic causation.
An example of something that is highly heritable but which we know is not genetic is language. Virtually everyone speaks the language of their parents, but we know that language is not transmitted via genes inherited from those parents.
Hi Daedulus2u & brian –
A few years ago I read “Guns, Germs, and Steel”, by Michael Diamond. In it, among other things, he argued that a participating factor that native asians or south americans were shorter than europeans was the result of the relative protein content of their primary staples; rice and corn versus wheat or chickpeas.
In any case, that is a pretty neat book.
– pD
pD,
Yes, Diamond’s a wonderful writer. However, I was careful to limit my discussion to “variation of height within a population” rather than between populations.