The autism spectrum disorders (ASDs), including autism and its milder cousin Asperger syndrome, affect about 1 in 150 American children. There's a lot of evidence that these conditions have a strong genetic basis. For example, identical twins who share the same DNA are much more likely to both develop similar autistic disorders than non-identical twins, who only share half their DNA.
But the hunt for mutations that predispose people to autism has been long and fraught. By looking at families with a history of ASDs, geneticists have catalogued hundreds of genetic variants that are linked to the conditions, each differing from the standard sequence by a single 'letter'. But all of these are rare. Until now, no one has discovered a variant that affects the risk of autism and is common in the general population. And with autistic people being so different from one another, finding such mutations seemed increasingly unlikely. Some studies have come tantalisingly close, narrowing down the search to specific parts of certain chromosomes, but they've all stopped short of actually pinning down individual variants.
This week, American scientists from over a dozen institutes have overcome this final hurdle. By looking all over the genomes of over 10,000 people, the team narrowed their search further and further until they found not one but six common genetic variants tied to ASDs. This sextet probably affects the activity of genes that connect nerve cells together in the developing human brain.
At the head of a 56-strong team, Kai Wang, Haitao Zhang and Deqiong Ma scanned the genomes of people from two different samples. The first was a group of 3,100 people from 780 families, all of whom had a history of ASD and at least two autistic children. The second included over 1,200 people with ASDs and about 6,500 normal people without any sign of the disorders.
The team looked at over half a million possible genetic variants in the DNA of all these people and found six that were consistently more common in people with autism than those without it. Each of these conveys only a small risk of developing autism, but they are common enough to make their influence felt in the wider population. In fact, they may play a part in around 15% of autism cases.
All of these variants hailed from the same location, a short stretch of DNA on the fifth chromosome that contains no genes itself, but sits between two of them - CDH9 and CDH10. Both are members of the cadherin gene family, which produce proteins that sit at the surface of cells and help them stick together. When brain cells develop, the cadherins are involved in creating synapses, the junctions between neurons that carry signals from one to another. As such, these genes are incredibly important for the correct development of neurons and indeed, they're only activated at very low levels in other types of cells.
The variants that Wang, Zhang and Deqiong identified sit within a "gene desert". None of them form part of any actual genes. Instead, the researchers believe that they may be part of sequences that control how surrounding genes - like CDH9 or CDH10 - are activated or used. CDH9 doesn't appear to be strongly activated in the brain, but CDH10 is a different story. When a foetus is just 5 weeks old, CDH10 is strongly active in its frontal cortex. This part of the brain controls many of our higher abilities, including our social behaviour.
It's tempting to suggest that neurons fail to hook up properly with one another in brains that harbour these six mutations, because they disrupt the work of CDH10. That fits nicely with the results of brain-scanning studies, which have also found a dearth of neural connections in autistic brains.
It's more than likely that other genes involved in sticking cells together have a role in autism too. The team went back to their data and looked at genetic variants that are possibly linked to ASDs but didn't make the cut as strongly as the six they focused on. When they looked at the positions of this B-list, they found that many were associated with a group of 25 cadherins, and 8 genes from the neurexin family, another group that helps to glue neurons together at synapses.
The same researchers have also looked at parts of the genome that are duplicated or deleted from person to person. These "copy number variations" have been implicated in autism before and the team studied them in about 2,200 children with ASD and 2,500 without it. Again, they found many of these variants are linked to cadherins, neurexins and other genes involved in cell connections. Others belonged to the ubiquitin family, which are involved in destroying other proteins, including those that stick cells together.
Together, these studies have painted a wonderfully coherent picture, linking observations of genetics, brain development, and behaviour. The authors have understandably hailed the work as a major breakthrough in autism genetics. They're confident in their results, for this is the largest study of autism genetics to date, and every one of the six variants that the team identified was confirmed in two independent samples of people (including about 1,600 more cases of ASD between them).
It's also a big win for so-called genome-wide association studies, which try to look for scour the genomes of thousands of people for common genetic variants that increase the risk of disease. These studies have been recently pilloried for being wasteful and expensive (although ably defended by the excellent Daniel Macarthur of Genetic Future). But, as this work shows, massive studies like these are necessary. Autism-spectrum disorders are so complex that studying their genetics with smaller sample sizes would be like peering at a landscape through a keyhole.
Reference: Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J., Abrahams, B., Salyakina, D., Imielinski, M., Bradfield, J., Sleiman, P., Kim, C., Hou, C., Frackelton, E., Chiavacci, R., Takahashi, N., Sakurai, T., Rappaport, E., Lajonchere, C., Munson, J., Estes, A., Korvatska, O., Piven, J., Sonnenblick, L., Alvarez Retuerto, A., Herman, E., Dong, H., Hutman, T., Sigman, M., Ozonoff, S., Klin, A., Owley, T., Sweeney, J., Brune, C., Cantor, R., Bernier, R., Gilbert, J., Cuccaro, M., McMahon, W., Miller, J., State, M., Wassink, T., Coon, H., Levy, S., Schultz, R., Nurnberger, J., Haines, J., Sutcliffe, J., Cook, E., Minshew, N., Buxbaum, J., Dawson, G., Grant, S., Geschwind, D., Pericak-Vance, M., Schellenberg, G., & Hakonarson, H. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders Nature DOI: 10.1038/nature07999 Glessner, J., Wang, K., Cai, G., Korvatska, O., Kim, C., Wood, S., Zhang, H., Estes, A., Brune, C., Bradfield, J., Imielinski, M., Frackelton, E., Reichert, J., Crawford, E., Munson, J., Sleiman, P., Chiavacci, R., Annaiah, K., Thomas, K., Hou, C., Glaberson, W., Flory, J., Otieno, F., Garris, M., Soorya, L., Klei, L., Piven, J., Meyer, K., Anagnostou, E., Sakurai, T., Game, R., Rudd, D., Zurawiecki, D., McDougle, C., Davis, L., Miller, J., Posey, D., Michaels, S., Kolevzon, A., Silverman, J., Bernier, R., Levy, S., Schultz, R., Dawson, G., Owley, T., McMahon, W., Wassink, T., Sweeney, J., Nurnberger, J., Coon, H., Sutcliffe, J., Minshew, N., Grant, S., Bucan, M., Cook, E., Buxbaum, J., Devlin, B., Schellenberg, G., & Hakonarson, H. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes Nature DOI: 10.1038/nature07953
Images: by Connie Kasari
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Great post. Thanks for sharing.
That's very interesting and it shows how cooperation among these many scientific institutions can make looking for a needle in a haystack possible. Still-there is so much more to do. This explains only 15% of autistic cases and only in the sense of a strong genetic association, not in how it happens or what sets off the autistic potential.
Awesome post. I've been doing a series on Autism myself, and this is exactly the kind of research people need to see!
Fantastic coverage as always, Ed. My own take on the study is a little less upbeat - I now feel like I'm betraying my "GWAS defender" reputation!
Hereâs my take, including, as I note on Skepticâs Dictionary, that the increase in Aspergerâs is in fair part due to a definitional change from DSM-III to DSM-IV.
I also note that a study like this is tentative, and may, if nothing else, show the need for tighter p-values in medical research. (For which need of tightening, plenty of other medical research also shows the need.)
I knew that each case of ASD is very special, but I found it surprising, that it can depends just on a single 'letter'. I wonder how it determines disorder's level?
If there is so huge variety in cases of ASD is it possible to find one 'general' medicament (working on frontal cortex as a whole) or it would rather be few more specific cures to soften symptoms?
I hope that the answers will be found soon, as '1 in 150 American children' is pretty much.
What's in a name? ASD includes autism, Aspergers, PDD, etc. The scientists found some of the ASD people had a genetic component. But the headline only mentions autism. This is misleading.
Autism and Aspergers are lumped into ASD together, but they have different causes and different symptoms. Autists can't talk; Aspergers don't feel like talking, but when they do they are eloquent. Autists lose house training; Aspergers don't.
Autists can be healed by dealing with heavy metals in their systems. It is not genetic at all. The Mennonite communities have no cases of autism; they don't take vaccinations with mercury preservatives. There are numerous testimonies of healing from autism on the chelation forums.
Aspergers is a genetic difference that is passed down through the generations and can only be compensated for. I've got Aspergers. We are not idiot savants; we think differently than the normal population. We are geniuses in our areas of expertise.
Can Aspergers also get autism? Yes, we can be affected by heavy metals as well as having the genetic difference.
Unfortunately, you're incorrect about the cause of autism. The mercury-autism link is not supported by the vast majority of research, and what little support exists is of low quality & suspect. Vaccines don't contain mercury anymore, yet autism still exists. Also, testimonials do not equate to scientific data; there are far too many confounders and sources of bias.
Also Timuchin makes a number of incorrect (or at least very generalised) statements about people with Autism and people with Asperger's in his comment. If he knew anything about ASD, he would know that it is a spectrum. Not all people with Autism have a problem with talking or with house training, they certainly don't "lose" it. Certainly no person with Asperger's that I've met has been eloquent. A bit of wishful thinking on his part perhaps?
@JP : Thanks for the shoutout :-D, I'm very glad that some people have found the series heloful.
@Timuchin: Admittedly, ASD is complicated, and the causes not entirely known. This is a good example of the of research that could lead to answers.
No study has shown ASD of any sort is caused by heavy metal poisoning. Many people who make this claim make their money off of chelation therapy. This is a dangerous therapy, that is demonstrably not helpful in patients with ASD.
The Mennonite communities have no cases of autism; they don't take vaccinations with mercury preservatives
The Mennonite community is also a very limited genetic pool. How would you differentiate a genetic cause from an environmental or other cause?
The same goes for almost every limited isolated group that supposedly has no ASD.
There are numerous testimonies of healing from autism on the chelation forums.
Unfortunately, ASDs are complicated. Their course is variable. That means that things don't always stay the same, many people improve on their own, or get worse on their own.
Those testimonials don't really prove anything, because odds are good that the people testifying would have improved anyway. Those people who didn't improve, don't testify. It's a form of survivorship bias. Thats one reason that science is important to tell us what treatments are useful.
My apologies for the textbook of a reply!
I thank "Science Blogs" for not banning me and deleting my post. The powers that be have often been that nasty. Especially when billions of Dollars of potential lawsuit claims are at stake.
As for research, the medical companies are paying for scientific-looking studies to defend themselves, and ignoring or denigrating all studies that show them to be liable.
The Mennonites are not some tiny group in Waco Texas that is having trouble with inbreeding. They are a large number in settlements all over the country. People come and people go from their settlements. They are the exception to getting vaccinations and in getting autism. That's the only difference. They have been researched for autism by doctors.
Science depends upon noticing numerous coincidences and checking for correlations. This is how medicines were found among backwards tribes off in the jungle. Those who wish to suppress the large correlation between vaccines and autism are being anti-scientific.
Before I knew I had Aspergers three years ago, I knew very little about autism and Aspergers. As an amateur scientist I quickly made up for that deficit.
The autism part of ASD is a spectrum of how much damage has been done so far. Chelation has a positive correlation with reducing the severity of the Autism.
If the pregnant mother is talked into having a battery of shots with ethyl mercury in them and the baby doesn't die, the baby can come from the womb with autism.
If a child is given a battery of shots (to save time), within one week the child often regresses into its own little world and can't talk anymore. This is a major correlation that the medical companies and their shills do their best to disparage. It doesn't take rocket science to see the correlation; it just takes a clipboard and a questionnaire. And a thick hide to put up with the anti-scientific shills.
The next tactic the anti-scientific shills come up with is to say that we must protect the "public confidence" on vaccinations so we don't end up with a "vaccine disaster." But the vaccinations are already losing their effectiveness. The hospitals are becoming dangerous places to go for surgeries. There is no vaccine protection against the swine flu that is spreading across the world right now. Honesty is the best policy.
As Daniel MacArthur notes, the common genetic variant is found in 65% of the autism cases, but were also found in 60% of the control group. The control group was of European ancestry,while the AGRE group are of mixed ethnicity.
Common genetic variants tend to skew differently by ethnicity and gender. The most extreme skewing is the presence of 'XY' sex chromosomes with a male - female ratio of 100% (males) to 0% (females).
The male:female ratio in autism has been reported to be anywhere from 3:1 to 9:1 depending on the study. I couldn't make sense of the demographics of the control group, perhaps you might be able to, but if the control group of European ancestry was not representative of the high male-female ratio reported in autism, one can only conclude that the control group was not representative of the autism group and the small difference between autistics (65%) and controls (60%) could be entirely explained by differneces in ethnicity and gender.
I hope you can inform the readers of the dempgraphics of the control group.
Sorry for the triple posting. Science writers including this blog, fail to heed Einsteins's dictum of having 'a passionate resistence to the dogma of authority'. The primary author of this study has been making the rounds of network and cable news claiming that 65% of autistics have this genetic mutation. In none of his network appearances has he disclosed that the same genetic mutation was found in 60% of the control group. Nor was he asked by 'science' writers'.
What conclusions would the general public make based on this type of reporting?
The Mennonites are not some tiny group in Waco Texas that is having trouble with inbreeding. They are a large number in settlements all over the country. People come and people go from their settlements.
Simply, patently untrue. They may not be some tiny group in waco texas, but they are absolutely an isolated genetic population.
They are the exception to getting vaccinations and in getting autism. That's the only difference. They have been researched for autism by doctors.
Ah, research, post a citation then. Because if there is no citation, there probably was no research. If you mention Mayer Eisentien, I'll point out that he has refused to publish the "findings" that he has few patients with autism, and refuses to return calls to researchers who have said they'd be willing to do all the work to attempt to prove his point.
But the vaccinations are already losing their effectiveness.
The only way in which vaccines are losing their effectiveness is that some groups of people aren't using vaccines. Vaccines work in societies by herd immunity - a very large percentage must use the vaccine to protect those who haven't.
The hospitals are becoming dangerous places to go for surgeries.
A lie, AND a complete nonsequitor. A lie because, hospitals are as safe, or safer than they have ever been. They are not "becoming" dangerous. A nonsequitor because none of the significant causes of mortality in the hospital, especially after surgery, were ever prevented by vaccines.
No one is saying vaccines will eventually prevent every disease. But they are very good at preventing diseases where there is a vaccine.
There is no vaccine protection against the swine flu that is spreading across the world right now.
Stupid example, the H1N1 swine variant is new! There could be a vaccine as early as the fall. If there is, I'll be taking it.
Honesty is the best policy.
I agree, honesty is the best policy. Honestly, you haven't read anything about immunology before posting about it. You haven't read the links that people referred you to to recieve more information. You're trying to scare people with irrelevant information.
The supplementary data for this study is now available:
The autistic group selected based on European ancestry was highly skewed to males (males=83%) (females (17%).
The control group selected based on European ancestry was Male (52%) female (48%)
Nowhere in the study was there a segregation of males/females.
Common genetic variants often are skewed by gender. Some comon genetic variants are more common in males while other common genetic variants are more common in females.
Does anyone consider the control group as a representative sample?
According to "Whitecoat Tales," he is a third year med student whose only knowledge of ASD is through his university. His university gets lots & lots of money from the pharmacy companies. He obviously has not read the links that people have posted on his own blog.
The mercury preservative that is still used in vaccinations should be replaced with something less lethal like arsenic or potassium cyanide. Google "minimata disease" to see the extreme symptoms of mercury poisoning.
Aluminum is called "adjuvant" in vaccine mixes because it causes the body to go on full alert. Not surprising; it as well is poisonous. No doctor knows what excess aluminum from a battery of shots does to the body.
For shame Timuchin ad hominem lately?
According to "Whitecoat Tales," he is a third year med student whose only knowledge of ASD is through his university.
I am a third year med student. My knowledge of ASD is NOT through my university. It is through science. Throughout my blog I have posted thorough references to science literature on the subject.
His university gets lots & lots of money from the pharmacy companies.
Pharma. Shill. Gambit. Since I blog anonymously, you have no idea what university I go to. You therefore have no idea IF they accept money from pharmaceutical companies at all.
Even if my university DOES accept money from pharma companies, I see no way in which it invalidates my posts, since a)I don't get any money from big pharma, and b)I reference primary science literature.
He obviously has not read the links that people have posted on his own blog.
For shame. You obviously haven't read my blog. I have responded to every vaccine denialist claim made on my blog, by reading their links, and correcting the mistakes found within.
The mercury preservative that is still used in vaccinations should be replaced with something less lethal like arsenic or potassium cyanide.
Disappointing. Thimerosal is no longer used in vaccines. It has never been proved to be dangerous at all, let alone as dangerous as arsenic or potassium cyanide. You have crossed the line from "ignorance" to "malicious disinformation."
Google "minimata disease" to see the extreme symptoms of mercury poisoning.
For shame. Minimata disease is mercury poisoning from MASSIVE DOSES of mercury. The doses seen in minimata disease are literally millions of times higher than recieved in the entire vaccine schedule. Infact, a few tuna sandwiches put more mercury in your body than vaccines do.
Aluminum is called "adjuvant" in vaccine mixes because it causes the body to go on full alert. Not surprising; it as well is poisonous.
Learn immunology before you make claims about it.
No doctor knows what excess aluminum from a battery of shots does to the body.
Argument from YOUR ignorance is not an argument. Just because you don't know doesn't mean doctors don't know. "excess aluminum" is incorrect. If you've ever eaten a small amount of aluminum foil on an overcooked piece of pizza you've had more aluminum than is in a battery of shots. Chemisty is far more complicated than you're making it. A quick pubmed search on aluminum will tell you all about what aluminum toxicity is. It only occurs at doses multiple orders of magnitude higher than those given in vaccines.
I sugest you do your homework before you post here. Don't let your beliefs get in the way of learning.
To judge between "Whitecoat Tales" and myself, google
1. "mennonites autism"
2. "flu vaccines Thimerosal"
3. "battery of vaccinations"
4. "adjuvant aluminum"
5. "alzheimer's aluminum"
This ain't rocket science.
Oh yes please do that. Because, of course, if lots and lots of websites say the same thing, it must be true. Makes you wonder why academics bother with references, peer review and actual experiments when they could just settle long-standing debates with GoogleFight.
Timuchin, I think we've wasted enough time on your incessant drivel. It's now getting very boring. Goodbye.