• Mon, Aug 27 2007

On Autism Genetics

Eye on DNA quotes Dr. David Levin in an article, The Genetic Journey in the Johns Hopkins Public Health Magazine feature:

The existing approaches and tools of genetic epidemiology work well to identify responsible factors when you’re dealing with diseases caused by a single mutation. They don’t work so well for complex diseases involving multiple genetic and environmental factors—some of the major public health problems in the U.S., like obesity, heart disease and Alzheimer’s [my emphasis]. To my mind, there’s a need for population-based and laboratory-based sciences to coalesce and develop new approaches to complex disease causation [my emphasis]. The first step is to train people in interdisciplinary ways so they understand the molecular sciences as well as epidemiology and biostatistics.

Dr. Levin’s views on the need to consider interdisciplinary approaches to “complex disease causation” might also be applied in regard to theories of autism aetiology. Says Anthony Monaco, Director and Head of the Neurogenetics Group at the Wellcome Trust Centre, one of the leaders of the Autism Genome Project (AGP):

“The probability has always been that autism is highly genetic, but highly heterogeneous – that lots of different genes are involved. We now have a great chance of picking them up.”

Prof. Monaco is quoted in an August 27th article in the TimesOnline entitled Hunting the gene that traps children in their own world. While describing autism as “devastating” and, in its opeing paragraphs, as a “controversial and feared medical diagnosis” and a “cruel condition,” TimesOnline makes connections between new findings on autism and genetics published earlier this year. From these studies on genetics, it is suggested that autism may not be a single disorder

The first genetics study was conducted by the AGP and involved over 1,000 families. Entitled Mapping autism risk loci using genetic linkage and chromosonal rearrangements and appearing in Nature Genetics, the five-year study suggests that autism has “numerous genetic origins rather than a single or a few primary causes.” DNA samples from 1,168 families—”the largest cohort yet of ASD families yet assembled”—with two or more autistic children were analyzed.

The second genetics study was about spontaneous (de novo) mutations. Under geneticist Michael Wigler of Cold Spring Harbor Laboratory in Long Island, NY, researchers studied families who have two or more autistic children and considered what the chances were for families whose first two children were autistic to have a third autistic child. Wigler and his research found that mothers spontaneously acquire genetic mutations that are specific for autism. While the mothers themselves do not have autism, there is a 50% chance that they will transit the autism-related mutations to their children. There are, therefore, families who are at a “low risk” to have an autistic child, and families who are “high risk” (in which the mother carries the mutations but does not show autistic symptoms). Notes the TimesOnline:

“Sporadic autism is the more common form of the disease and even the inherited form might derive from a mutation that occurred in a parent or grandparent,” the professor said.

If mutations of this sort are responsible, they would not show up in the AGP: they are new and unique to individuals and families, so will not surface from large comparisons of DNA.

Additional genetics research is cited to suggest that autism may not be a single disorder: Angelica Ronald, Francesca Happé and Robert Plomin, of the Institute of Psychiatry, have suggested that different sets of genes may influence each of the three criteria used to diagnose autism (social difficulties, communication difficulties, and behavior issues):

This has important implications for gene-hunting. It could be that genes have not been found because scientists have been treating autism as a whole. If different genes affect the communication and social elements of the disorder, finding them might involve looking at people who are not autistic, but who have mild versions of one of the problems. “We need to tackle whether we should look at autism as a single phenomenon, or whether it would be better to look, for example, just at autistic social problems,” Dr Ronald said.

Dr. Ronald also notes that learning more about the genetics of autism can help greatly in diagnosis and treatment. For myself, the more I learn about autism genetics, the more I see how Charlie is connected to Jim’s and my families, and how very much he shares with all of us.

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  • http://laurentius-rex.blogspot.com laurentius-rex

    I commented on this in the Times thuswise :

    Again the press treats autistic people as less worthy than other disabled people of having our condition accurately described assuming we do not have a voice to answer to this characterisation of us as something so negative that it is better we were never brought into the world.

    Language and metaphor is used in a way that would not be deemed suitable when talking about other groups of disabled people, who have through the disability movement made progress in terms of seeing the social model of disability widely adopted.

    Genetics is a very complex subject and despite of the hype the mathematical complexity of uncovering a genetic cause for autism is going to cause confusion for some time.

    There are many studies, but what is not often published amongst the hype is the degree to which these various studies contradict each other, often because of small sample sizes and poor controls. One group says it is in the fathers genes another the mothers etc.

    It does not add up.

    I am not sure they will put that comment up.

  • http://www.autismvox.com Kristina Chew, PhD

    Am glad you included it here.

  • bullet

    Personally it seems to be in my genes. My dad has a lot of traits, but isn’t on the spectrum. My mum has some traits (I suppose a similar outlook to things kept them together). My younger sister doesn’t appear to be anywhere near the spectrum, but my older sister has some traits. I am Aspergers and my older son is autistic. I long for an article that acknowledges parents can be on the spectrum as well as their children.

  • http://aoskoli.blogspot.com/ VAB

    Autism is such a broad term, especially these days, that I am sure there are difference causations in different instances. John might get his autism from three (or thirty) fairly unusual gene variants, while Jane get it from one unusual gene variant and six very common gene variants that happen to reinforce the one unusual one. Meanwhile Tim might have a fairly ordinary genetic make-up but may have developed atypically because of an event such as a viral infection.

    If this were true, it would not mean that there would not be similarities between John, Jane and Tim. They could share similar ways of feeling and thinking as the result of different adaptations in the brain, or they could have very similar adaptations in the brain as the result of these different causes.

    I am pretty sure that, when they do find a biological cause for autism, it will only account for a handful of the people who have that diagnosis.

  • http://autismnaturalvariation.blogspot.com Joseph

    I’ve only heard non-autistic people describe autism as “cruel” and such. I’m willing to bet that even autistic people who don’t like autism don’t see it in such ridiculously dramatic terms.

  • http://www.autismvox.com Kristina Chew, PhD

    I appreciated the Times’s article discussing recent genetic research on autism and trying to make some sense of it all—-to make connections. The opening paragraphs did not give me this sense; I was expecting more references to environmental factors than were the case. The article did also manage to use a number of negative, if familiar, references to autism (“cruel” etc.)—–

  • http://www.autismbites.com John Kirton

    We felt that we should help with the genome project and got involved through the University of Utah. Being as we still appear to have the most children on the spectrum in one family, six, we hope for results as to why.

    We love our children and accept who they are, but if a way can be found to reverse or ‘fix it’ we’ll sign up. And if some feel that attitude is somewhat harsh, well… you try dealing with 6 children from 13 to 2 with Autism. No picnic.

    We believe it has to be a combination of genetics and environment. My wife and I have no form of Autism. She has an uncle who we now believe is Aspergers and maybe a great-uncle, but that’s it. Where did ours come from?

    Until and likely past, we’ll deal with the poopy walls and floors, destroyed furniture, bitten DVDs, shredded mail, books and magazines, escaping screaming huggable angels sent from above.

  • http://www.autismvox.com Kristina Chew, PhD

    Angels, all, and always, however they come to us.

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  • http://homepage.mac.com/dgstevenson/ Donna

    Some think that autistic genes create quirky behavior that leads to people having children later in life, and then older parents would naturally have more random mutations of all types. I don’t understand how you know whether those varied mutations cause autism or are caused by autism.

  • http://www.mywaiora.com/132674 George Wade

    Joseph,

    Now that I am recovering from the mercury toxicity side of Asperger’s: I can see and feel it clearly enough to know that it has been very cruel.

    In many ways a wasted life… But not in all ways: I did go sailing; got away from medical research, which was mostly a dead end; went to Japan and learnt to live from the beginning, again.

    The latest challenge is a wife who has taken 99.8% of the family assets and fled to the other end of the country. She doesn’t realise that recovery from Hg toxicity is possible and that I can fight without being vindictive…

    It has not been ridiculously dramatic: ridiculously boring and frustrating; horribly debilitating with colitis the last 25 years. Shocking to see an inability to think clearly or to remember, that one does not notice when sinking into the toxicity but sees all too clearly on the way up and out of it.

  • Patrick

    What a nice testimonial from a multi level marketer George!

    Why don’t you have that company get a peer reviewed study done and published and have the government(s) provide the product to those of us who need it for free, hmmm?

  • http://www.mywaiora.com/132674 George Wade

    We are having a clinical trial done, Patrick, funded by the line I’m in; if it gets peer reviewed that would be a bonus: but the doctors involved are hard headed enough that the evidence they find will be perfectly useful.

    We can count on the governments of most of the world not providing the zeeolites free of charge, for the next 50 years; so I’m having to be a nasty, profiteering MLM’er for a few years to build up a fund to support you guys in need. -:)

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  • Larry

    The newest studies suggest there is no gene for autism (At best there is might be a gene for a predisposition to neurosis). It turns out that identical autistic twins everybody refers to are the cause of autism, not evidence of some peculiar neurobiology. I swear I’m not making that up. Look at this:

    http://news.bbc.co.uk/2/hi/health/1949329.stm

    People can’t see the forest for the trees. Either that, or politics again is the cause of hysterical blindness. The psychology of autism researchers themselves is suspect. It goes something like this: We MUST find a genetic cause for autism. Therefore autism is a genetic disorder.

    Kanner’s suggestion that autism may be genetic was PROVISIONAL. That hypothesis has not stood the test of time. It’s time for a someone with both intelligence and courage to save the children. That rules out most modern researchers.
    ——-

    “It was notable that all the children who suffered setback regressed between 15-27 months. This does seem to be a particularly vulnerable period of development, with a number of other conditions (eg, Rett syndrome, tuberous sclerosis, some cases of autism in the sighted) becoming apparent at around the same time.
    This information can be integrated by the hypothesis that the onset of regression is triggered in neurologically vulnerable children by a constellation of environmental conditions (that are in some way suboptimal for a blind child) occurring at a critical stage in the development of attention control and social interaction (see figure 8).
    Figure 7
    Figure 8
    4 A Worrying Dilemma
    This explanation gives rise to a serious dilemma: On the one hand, many people working in the field of autism are understandably disturbed by any aetiological explanation which has an environmental component, fearing a resurgence of the outdated and damaging “refrigerator parent” theory. At the same time, many educators and therapists with extensive experience in the field of visual impairment are unhappy about rationalisations which are based on a pre-programmed neurological theory, feeling that this does not intuitively hold true for the children under their care.”

    -Scottish Sensory Center

  • http://www.autismvox.com Kristina Chew, PhD

    It is not a matter, it seems, of a single gene for autism; studies show that many genes are most likely involved.

  • Cliff

    I don’t think the genetics are that one-sided, and I don’t think the argument ever was “We must find the genetic component, therefor the genetic component exists”.

    And, last I checked, there were implicated genes (note the plural) in the development of autism, as your link noted.

    Also, even considering faternal twins, genetics have been seen in such a way that they implicate the liklihood of siblings being autistic, so I don’t think the faternal twins are different. In fact, I don’t see where the logic really follows, in the end, that twins=environmental factors.

    Also, what exactly is the Scottish Sensory Center (I know nothing about it).

    Cliff

  • Larry

    Here is a link to the Scottish Sensory Centre:

    http://www.ssc.education.ed.ac.uk/aboutSSC/about.html

    The cautious language used in the report is itself evidence that SSC scientists are not quacks.

    The logic of the twins study is this: If simply being born a twin–regardless if the twin is identical–makes one predisposed to autism, then the argument that identical twins are evidence of a genetic link are out the window.

    In other words, there is no genetic predisposition to being born a twin, but being born a twin means you are more likely to be born autistic. Therefore, by logic, there is no evidence here of genetic predisposition to autism. The fact that there is a higher incidence of autism in twins that are born identical might suggest a vague and mysterious genetic determinant, but it also might suggest an increase in stressful womb competition–as the researchers pointed out. There is, in fact, plenty of statistical evidence that stressful birth is linked to autism.

    http://www.wombecology.com/caesareans.html

    http://www.medicalnewstoday.com/articles/24689.php

  • Larry

    Incidentally:
    Here is the entire report from the SSC regarding autism in blind children:

    http://www.ssc.education.ed.ac.uk/resources/vi&multi/hcass96.html

  • http://www.autismvox.com Kristina Chew, PhD

    Thank you for the links. What I see most in my lived day to day experience with my son is how there are patterns of similarity in how he learns and understands and expresses himself, and various aspects of my husband and me. Do you have an autistic child?

  • Larry

    I am autistic, but none of my three children are.

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  • Tonya

    My husband and I are looking to adopt a baby. The agency has found a birthmother for us having a little girl. She has 2 boys, both have autism. TThe birthfather is different than the father of the two boys. I hope someone can tell me what the the chance is of this child of having autism. A prompt response is appreciated. Thanks!

    Tonya

  • nym-d out

    Tonya:

    In what way are you concerned? I mean about “the chances”?

  • http://www.autismvox.com Kristina Chew, PhD

    Tonya: How old is the baby—-have you seen how she interacts and plays?

  • larry

    There are no experts on this subject. No gene, or gene complex, has been isolated for autism. And no single environmental determinant has been identified.

  • http://www.autismvox.com Kristina Chew, PhD

    A website called Exploring Autism tries to pull together what is known about autism genetics. Go here for a list of Frequently Asked Questions.

  • http://crimsonthoughts.spaces.live.com/ Cliff

    Interesting site, Kristina. Thank you for that.

    Cliff

  • larry

    The project refers to studies made between 1997 and 2002…

    Also, there is a definite link between autism and genius–precociousness at birth. That sure enough is genetic. But not all autistics are Rain Man.

    There is also a definite connection between celiac disease which also is probably genetic.

    Also milk allergies are associated with autism.
    Those are genetic I think.

    Unfortunately there are also definite links between autism and environmental determinants like caesarean birth and premature birth and blindness and traumatic reaction to vaccinations.

    Any one of the above will increase the statistical chances your child will be autistic.

    Genetic testing won’t help you even a little bit, but at least you can check out the above risks to help you decide better.

  • nym-d out

    Link for Larry:
    http://www.advicegoddess.com/mt/mt-comments.cgi?entry_id=4563
    I ran into this last night and thought of you.

  • larry

    Thank you so much. I think I will post something rude. People who resort to cheap scorn aren’t worthy of a reasoned reply.

  • Ms. Clark

    The odds are that every single baby needs parents who are utterly devoted to it – no matter what. Parents who are worried that the baby might not be right, might not make the right kind of parents for any baby, especially one that might be high maintenance.

    Girls are less likely than boys to get ASD dx’s but that’s across a whole population. A family that already has two boys on the spectrum would have a higher rate than typical even for a girl, but I have no idea what that would be. I would guess quite a bit less than 50/50, but that would depend on the genes the mom has, if she, for instance is a Frag X carrier, which could be… then she’d have a 50% chance of having a girl who would be more mildly affected than her brothers (statistically).

    I don’t know of any study showing higher number of celiac people among ASD folks. I just heard today that the rate for celiac in all of Italy is 6%. They test for it at birth! Amazing.

    I think 90% of Freudian psychology is utterly riduculous, but then, that’s just me. I think dream interpretation is about as meaningful as homeopathy. :-)

  • larry

    Somebody just posted this brilliant opinion:

    “I think 90% of Freudian psychology is utterly riduculous, but then, that’s just me. I think dream interpretation is about as meaningful as homeopathy. :-)”

    Twenty-three volumes of Freud’s work is still in publication in paperback. An entire branch of medicine–psychoanalysis–is based on Freud’s “Interpretation of Dreams.” Much of this work is still required reading in medical schools all over the world.

    I wonder which volumes in particular are in the ninty percent utterly ridiculous.

  • http://www.autismvox.com Kristina Chew, PhD

    Back to the topic of the post: Data on genes collected from 3000 individuals with autism or from their family members has been released today (October 22nd) by the Autism Consortium. Researchers used Affeymetrix microarray techology to provide “comprehensive view of the genome, enabling researchers to analyze 500,000 markers simultaneously and perform whole-genome analyses in large populations.”

  • larry

    How long did they think it will take to isolate a gene or gene complex for autism? If such a thing exists, that is.

  • larry

    I’m willing to bet that any gene they find will appear in only half of all autistics. Furthermore, I’m willing to bet lots of money that the same gene will also be found in half the people suffering from plain old run-of-the-mill neurosis. Just like Freud suggested.

  • http://laurentius-rex.blogspot.com laurentius-rex

    One gene, only one? eugene onegin I dunno.

    I am willing to bet something else

    Just as any particularly complex number can be factored in a multitude of different ways and summed in even more, so will it be with Autism.

    There will be different combinations not all of the same genes which all lead to the same result.

    Humanity in all its diversity.

  • http://www.autismvox.com Kristina Chew, PhD

    eugene one-gin — sorry, could not resisting seeing more puns!

  • http://www.autismvox.com Kristina Chew, PhD

    Hi Tonya, Some more information: The prevalence data on siblings is estimated to be 5-10%—from that, overall, there is a 90-95%
    chance that this child will not have autism. There are, though, some data that suggest that siblings of children with autism have slightly increased rates of language and/or social
    difficulties that are much more mild than autism.

  • larry

    Has anyone seen the recent NOVA episode on epigenetics?

    http://www.pbs.org/wgbh/nova/genes/expert.html

    The webpage doesn’t mention one particular experiment that was shown on TV. It was really, truly threatening to conventional wisdom. It turns out that identical twin mice developed a *genetic* susceptibility to various mental and physical illnesses based on the amount of nurturing they got from their mothers. I swear I’m not making that up. This contoversial bit of information has been removed from the website, but it is still being shown on T.V. Those producers are going to catch hell.

    If the scientists prove right, then everything about autism will be explained, and it will be none other than Bruno Bettelheim who will be vindicated.

    I mean even Bettelheim never went so far as to even imply what these guys are saying!

  • larry

    Here’s a better website on the subject:

    http://www.mcgill.ca/headway/fall2006/indepth1/

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  • larry

    OK. You win the argument, but so do I. It’s a crazy situation.

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