Autism and Genetics: What We’ve Got Here is a Failure to Replicate
By Mark Blaxill
In a break with past practice, publication of a new full genome autism study was just announced with relatively little fanfare. Published today by the highly prestigious journal Nature, this new study by the Harvard based Autism Consortium was released with almost none of the promotional hype and editorial celebration that we’ve typically seen in studies of this type. To be sure, the investigators put on a brave face and claimed success in discovering yet another new “snip” (aka SNP, for single nucleotide polymorphism) that they claim to have located near a neuronal gene called semaphorin 5A. The fact that it’s not on any actual gene is critical, since that means they have no idea what biological function might be going awry in autism. But as the standards for judging autism gene findings have progressively degraded, even though the positive finding is not exactly on the gene, it’s close enough. Because if close is good enough for horseshoes and hand grenades, that must be good enough for genes and autism too.
But what is most striking about this report is a little nugget buried deep in the paper. Age of Autism readers may remember the last big autism gene study that I wrote about earlier this year (see HERE). That study, conducted by Paul Offit’s friends at the Children’s Hospital of Philadelphia (CHOP), reported that a common genetic variant was found more frequently in autistic genomes. More specifically, a DNA sequence in between two genes on chromosome 5p14 (again, this finding was just near the known genes, not on them) that was present in 61% of normal controls, was present in 65% of autism cases.
Now, if you're like me, you may not find that difference particularly earth shattering: the idea that the most prominent “abnormal” gene in autism is present in 61% of the neurotypical population. But that didn’t stop the celebration at the time, this finding was presented as one of the great breakthroughs of modern autism research. Not surprisingly, therefore, the Harvard group looked at the same region in their latest genome scan. Here’s what they reported.
During review of this manuscript, another genome-wide association study was published which identified significant association to SNPs on chromosome 5p14. Although there was significant overlap between study samples, each of these scans contained a large set of unique families, so we sought to evaluate independent evidence of the top SNP (rs4307059) reported at 5p14…[W]e observed no support for association at this locus..[and instead found a gene transmission frequency] in favour of the minor allele, a trend in the opposite direction as reported.
In other words, paraphrasing the words of Cool Hand Luke, what we’ve got here is a failure to replicate.
Results like this are remarkably common in full genome autism studies, whether (like the latest one), they’re reporting on inherited genes or (like an earlier study from the Harvard group) genetic mutations called “de novo copy number variants” (CNVs). The plot is so familiar by now that it’s worth betting on. In response to the failure of the last round of gene hunts, a new research group raises money for the largest sample of autism families ever collected. They apply the latest technology, check their results with other samples and set the computers in motion. When the results come back, lo and behold, they find that virtually all of the prior “autism genes” don’t show up significant in the latest analysis; in fact, some of the highest and best hopes of the autism genetics community are dashed by negative findings. But some brand new shiny region emerges out of the massive number crunchers and this new “discovery” goes straight to the headlines.
The sad part, of course, is that the human genome is so large is that when one runs numbers like this you’d almost always expect to find a result that approaches significance somewhere on the genome. But the gene hunters continue to sally forth undaunted. And since no one in the medical press ever bothers to go back to read any of the previous studies, they’re more than happy to file a story celebrating the triumphant march of medical science.
The funny part is, the last time we saw this dynamic, it was the CHOP group dashing the hopes of the Harvard group, which had claimed to find a “hot spot” of genetic instability on chromosome 16 (an excessive rate of deletions on chromosome 16p11). In their study published in April of this year, the CHOP group tried to replicate this finding in a follow on study of de novo CNVs. Here’s what they reported.
“We observed a similar frequency of deletions and duplications of the 16p11.2 locus in the ASD cases (~0.3%) as previously reported; however the CNV frequency in the control subjects at this locus was also comparable to that of the cases.”
In other words, the rate of mutation was no different between autism cases and controls and the Harvard group may simply not have had a large enough sample to detect such a low rate of mutations in the normal controls, where the CHOP group found plenty of deletions.
So much for the hot spot.
So now we have another darling gene, semaphorin 5A. The gene hunters will add it to the list of “known autism genes”, but I’d be more than happy to take money from anyone who wants to bet that we’ll find it semaphorin 5A coming up positive in future studies. After all, no one ever found it before during years of searching, so why should we give this latest finding any more credence than a random number generator. Still, the thirst for positive results is strong in autism geneticists. That said, even the gene hunters are beginning to sound weary now. “It’s a nice finding”, said Mark Daly, one of the Harvard study’s senior authors “but it’s just a small step in what’s really the first step of addressing autism.” In yet another metaphorical plea for patience he remarked, “It’s a long road ahead, [but] at least we found the road.”
Autism rates are now up to more than 1% of American children, nearly 2% of boys. Genetic research is in disarray, reeling from years of incoherent findings and an incoherent logic that ihas become increasingly exposed. We all get tired of saying it, but it bears repeating that there’s no such thing as a genetic epidemic. Yet NIH continues to pour millions more of our tax dollars down the gene hunting rat hole and, in a trend that is even more disturbing, the new administration appears to be doubling down on the failures of the past.
In the face of such obvious irrationality from so many highly educated analysts, it’s enough to make you ask, do any of these people have a brain?
Mark Blaxill is Editor-At-Large for Age of Autism.
Jes, yes and no. In theory there need not be ANY specific inherited genetic marker involved for a disease to develop. In theory it could be sometimes down to shear number and volume of environmental insults piling up and reaching a boiling point after a while.
Posted by: Natasa | October 09, 2009 at 06:57 AM
"All of this info is valuable, including the genetic hunt. Unfortunately, the latter only goes so far. Harris Coulter told - with facts - the world years ago that yes indeed there was a genetic factor in kids with ADD/ADHD & ASD & such, since those conditions were found often to run in families; but the point was that it was a genetic predisposition to be damaged by vaccines/had an environmental trigger. The missing link, in the brains of these cretins who are running the medical show in our day and age."
thank you so much for that stan, i have been attacked many times for even hinting at the genetic link, there has to be disposition otherwise all vaccinated kids would be autistic! my dad had ms and my son now autism. i had no choice but to understand it is in my genetic makeup triggered by toxins.
Posted by: jes | October 09, 2009 at 12:39 AM
They have a brain but they also have wallets that get emptied fast and need to be refilled by a sugar daddy named Pharma.
Sadly vaccine damaged children and families do not refill wallets or bank accounts.
Posted by: Richard | October 09, 2009 at 12:07 AM
Great article! I believe they do have a brain. The sad news is that they are corrupt beyond belief.
Posted by: Mr. T | October 08, 2009 at 06:42 PM
Chickle,
Be aware that MSG (in the form of glutamic acid/hydrolyzed gelatin) is in vaccines as well as foodstuffs - and thus in an inflammatory setting to start with. It is in all live-virus vaccines (acts as a stabiliizer). As if that weren't bad enough, glutamate lowers glutathione levels as well; so giving the MMR, say, at the same time as the DPT, say, would tend to make it more difficult for the child to eliminate the heavy metals (Al and Hg) in the DPT.
As for glutathione levels: At least the search for genetic predispositions to ASD has uncovered the genetic polymorphism causing a subset of children to be low in those levels. Not that that info has made much of a ripple in the white matter of our authorities' brains, since it brings up the issue of the likes of Hg and Al in this matter. And also, speaking of glutamate & its effects: Carol Hornlein (of msgtruth.org) has pointed out that at least some of the early genes found to be associated with autism code for glutamate synapses; which factor makes this substance doubly dangerous for such children (since it already causes inflammation in the brain to start with). Glutamate is also high in gluten and casein - a main factor in why a GF/CF diet is so valuable for kids on the spectrum.
All of this info is valuable, including the genetic hunt. Unfortunately, the latter only goes so far. Harris Coulter told - with facts - the world years ago that yes indeed there was a genetic factor in kids with ADD/ADHD & ASD & such, since those conditions were found often to run in families; but the point was that it was a genetic predisposition to be damaged by vaccines/had an environmental trigger. The missing link, in the brains of these cretins who are running the medical show in our day and age.
No, vaccines alone are not the answer. But THEY ARE INVOLVED. The autism community should fight tooth and nail to make sure that monies for research into the causes of ASD do not get siphoned off into genetic studies in a big way, esp. at the expense of things like a vaxed-unvaxed study. The responsible (sic) authorities could stonewall this matter for years, if the community doesn't keep up the pressure on them to cast a wider net.
Yes, it's tiresome. Yes, progress seems slow at times. Yes, it's enough to make one scream. And good on you, parents, for picking yourself up and dusting yourself off and heading back into the battle again. Because it's worth it. And it WILL pay off. The truth, ultimately - the whole truth - will out.
And won't that be a great day. So give yourselves credit, for being the generation of parents who brought it about. By continuing to sock it to'em, and not giving up. For your kids' sake, and those to come.
Posted by: Stan | October 08, 2009 at 06:14 PM
With a nearly 100% compliance rate for vaccination among school children, who were the "neurotypical controls?" Maybe the reason there is "no difference" is because no one can escape the effects of vaccines entirely.
It's a good thing smart people like Mark are looking out for us! Thanks Mark for your insightful analysis.
Cynthia Cournoyer
http://www.whataboutimmunizations.com/
Posted by: Cynthia Cournoyer | October 08, 2009 at 12:36 PM
It is a mystery and no one can say for sure...All I know is my baby boy was fine until he received his MMR........
Posted by: K Bell | October 08, 2009 at 11:08 AM
"To your point, where in the freak did their brains go?!!"
JB...simple answer?
Up their a$$es.
Posted by: Craig Willoughby | October 08, 2009 at 08:02 AM
RNA editing appears to be the major mechanism by which ENVIRONMENTAL SIGNALS OVERWRITE ENCODED GENETIC INFORMATION to modify gene function and regulation, PARTICULARLY IN THE BRAIN. We suggest that the predominance of Alu elements in the human genome is the result of their evolutionary co-adaptation as a modular substrate for RNA editing, driven by selection for higher-order cognitive function. We show that RNA editing alters transcripts from loci encoding proteins involved in neural cell identity, maturation and function, as well as in DNA repair, implying a role for RNA editing not only in neural transmission and network plasticity but also in brain development, and suggesting that communication of productive changes back to the genome might constitute the molecular basis of long-term memory and higher-order cognition.
John S. Mattick and Mark F. Mehler. Trends in Neurosciences, Volume 31, Issue 5, 227-233, 1 May 2008
Posted by: Natasa | October 08, 2009 at 08:00 AM
So well said Mark. We can expect more of the same in future: US government is currently throwing more money towards genetic studies - this time it is the wholy grail of gene studies, the Whole Genome Association study.
Basically what they are saying is that so far we have not been able to find anything in (coding) DNA sequences that would explain autism in substantial any way. So lets look very closely at another 98% or so of the genome – the non coding parts.
The trouble is that once again they are going to look into mutations (ie passive codes) of the whole genome, completely forgetting how massively influenced and interactive these systems are with the environment. Especially in the brain!!
So instead of looking at FUNCTIONALITY of those systems, they are again looking at the passive, sleeping codes. Instead of spending more money looking at exogenous/non inherited non coding RNAs (for example viral ncRNAs) in the brain and other body systems in autism, instead of for example looking closers into how microbial RNAs and environmental toxins influence host DNA editing (for example through ADARs) … science will throw more money into Mendelian waste-bin, and will find itself scratching its head once again when the Whole Genome Association returns next to zero answers to autism *mistery*.
Posted by: Natasa | October 08, 2009 at 06:13 AM
I think it has to do with such food gems as MSG, Food Preservatives in general, and not just vaccine preservatives. MSG is the most horrific food additive, yet, the government won't stop it. With autism, you start reading every label. It is shocking the synthetic garbage in very basic food, from bread to milk, to meat.
Posted by: Chickie | October 08, 2009 at 03:06 AM
"do any of these people have a brain" I love it how your last sentence captures exactly what I was thinking the entire time I read your article, Mark.
These people are gyrating around a fixed object and can't see the forest for the trees. Maybe they should study genetics surrounding the dying breed of researchers with common sense.
Posted by: Elizabeth | October 08, 2009 at 01:58 AM
Hello Mr. Blaxell,
You've written a great article. Congratulations. I can only wish that money would be invested in studying one DIFFICULT study after reading your article: A study of autism incidence in vaccinated v. non-vaccinated populations. Since everyone "knows" that vaccines don't cause autism, this study should have been conducted years ago! Hmmmm... Why hasn't it been done yet? Why isn't Mayor Eisenstein bothered at his office? Why aren't any of the Amish of PA interviewed? maybe they can't find Chicago or Pennsylvania? I'm not sure! Maybe they they do not want to KNOW the real answers? Unvaccinated children RARELY if EVER, get autism! Yes, the truth might be painful to acknowledge, just like recognizing that "gene research" is a scam!
Posted by: Tom Petrie | October 07, 2009 at 09:20 PM
Mark:
Your incisiveness, coupled with dry wit, makes you a community treasure. I'd really like to hear from the others themselves - do they realize the utter worthlessness of the current knowledge of autism and genes? Do they ever scratch their heads and the growing rate of autism in this country and wonder, maybe, they are on the wrong trail? To your point, where in the freak did their brains go?!!
Posted by: JB Handley | October 07, 2009 at 09:15 PM
Check out this bull f-ing sh-t from the august Atlantic magazine!
http://is.gd/42V2k
Gee! Kindly pediatricians are overdiagnosing kids with autism so they can get access to all those wonderful free services and perks that kids with autism have!
I have to go on a news blackout because I am just too angry to function right now.
Posted by: julie | October 07, 2009 at 09:13 PM
Of course they have a brain, Mark. They know that searching for the magical autism gene is the way to get funding for study after study. It's a conscience that they don't have.
Posted by: Theresa | October 07, 2009 at 08:44 PM
Just wanted to add that a "cool" million or so could fund a comprehensive study on vaccinated compared to unvaccinated children (do not want to use "versus" as it sounds negative in this context.
Posted by: Teresa Conrick | October 07, 2009 at 08:43 PM
And their heads they'd be scratchin'
While their thoughts were busy hatchin'
If they only had a brain...
Thank you again, Mark. It really is pretty intriguing that the press hasn't jumped all over this one. I sense that editors are thinking like PR agents for industry and saying, "Look, enough time hasn't passed since the last 'big gene discovery'. It won't sell. Time your research a little better next time-- at least one year between 'big autism gene discoveries'. Give the public time to forget the last finding was shit, okay?"
Posted by: Gatogorra | October 07, 2009 at 08:16 PM
Great analysis of a bad and negligent trend. Pouring that money in the wrong places helps no one except these gene chasers and their ivy league competition. It is maddening and sickening to see millions wasted here instead of on case studies examining the children and their labs (high, dysbiotic bacteria; chronic viruses; abnormally high heavy metals; immune dysfunction; gut and brain inflammation---why do the powers that be - unfortunately, this current administration - not see this?)....that would be a fraction of a million but would reveal a wealth of information.
Not only do these guys have a failure to replicate (and communicate- ie, do true, pertinent, meaningful research) but their fruitless and inappropriate data is not preventing autism nor alleviating/curing our already sick children.
Posted by: Teresa Conrick | October 07, 2009 at 07:37 PM
Great job, Mark. After the CHOP study came out, touted in headlines as the "autism gene found", a young immunologist asked me if I saw that they found the autism gene. I asked him if he read that it appeared in 1% of those with autism. His reply was that, no, he had just read the headline.
Posted by: Laura Cellini | October 07, 2009 at 07:15 PM
It's amazing how many sites along a strand of DNA things like mercury and aluminum can disrupt.
Posted by: I812 | October 07, 2009 at 05:44 PM