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The NIMH Center for Collaborative Genetic Studies

17 Jan

I follow the Director’s blog at the National Institute of Mental Health (NIMH). A recent post is titled Looking forward to 2011

You probably won’t be surprised that I did a search for “autism” in the text. I only found one hit:

Genomics and Other High Throughput Technologies

What happened with computers in the last decade – faster, cheaper, better – is happening with technologies to sequence the human genome today. Once cost prohibitive, the price of DNA sequencing has dropped drastically in the past several years. Soon, whole genome sequencing will become the norm in research. With such precise methodology, this will be the year for discovering many new genetic variants associated with mental disorders. To expedite our discoveries, it will be key to share high quality data produced by these sequencing efforts and to build the computational resources to analyze the impending avalanche of data. The NIMH Center for Collaborative Genetic Studies has become the world’s largest repository for DNA samples from individuals with mental disorders and their families. In 2011, with samples from this repository, along with consortia developed with investigators around the globe, we should get our first comprehensive view of the genomic risk for autism, schizophrenia, and bipolar disorder.

emphasis added.

It’s an interesting hit. First, the director of NIMH is in a position to know what research is in the pipeline. If he says 2011 should give us our first “comprehensive view” of the genomic risk, I’m willing to bet that something will come out this year. More importantly, I was unaware of the Center for Collaborative Genetic Studies.

Leave aside the genetics part of this for the moment and just take a look through the site. It is a great idea. Making data from multiple investigations available to other researchers.

Here’s the “scientific mission”:

Scientific Mission

Given the major public health implications of identifying genes that contribute to the susceptibility for severe brain disorders, the National Institute of Mental Health (NIMH) has funded a Human Genetics Initiative. The goal of this Initiative is to study individuals affected with schizophrenia, bipolar disorder, or Alzheimer’s disease and their relatives, in order to establish a national resource of clinical/diagnostic information and immortalized cell lines for DNA extraction. These data and biomaterials are distributed to qualified investigators in the wider scientific community, for use in research on the genetic basis of these disorders. The NIMH Human Genetics Initiative is supported by the Office of Human Genetics & Genomic Resources in NIMH’s Division of Neuroscience & Basic Behavioral Science (DNBBS).

Progress in scientific understanding is best achieved by the free and open exchange of knowledge, data, and ideas. The NIMH Human Genetics Initiative was founded on the principle that timely access to primary data and biomaterials for human genetic research may stimulate research and development and maximize the benefits afforded to individuals affected with these disorders and their family members. Progress in these efforts is paralleled by growing interest throughout the scientific community in having timely access to the information and resources that may speed the understanding of disease etiology, refinement of diagnostic systems, and development of novel therapeutic agents and preventive interventions.

The autism page for the site gives a brief statement and links to the autism pages. You can see what papers have already come out of the autism consortium, including many available for download. They have data on sibling pairs, where genetic data on families with families with 2, 3, 4, even 5 ASD kids are included. They are up to revision 7 on the data. You can see what data are in the pipeline in the future releases page. There are a lot of data in the works, with a lot of it coming on line in the next year or 2.

The idea is great. I’d love to hear from researchers as to how well it really works. But the data, the raw data, are being made available to multiple researchers. There are other projects like this out there in autism research.

Mitochondrial Dysfunction and autism. Brief Q and A with lead author

13 Dec

Mitochondrial Dysfunction was thrust back into the news again earlier this month when a team from UC Davis led by Professor Cecilia Giulivi discovered:

In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children

In itself this is a fascinating development and the first true look at whether autistic children were more likely or not to have mtDNA dysfunction(s).

However, as ever in the world of autism, the world of the anti-vaccinationists are never far behind. This passage from Harold Doherty demonstrates this bizarre need to always conflate the two:

The Poling family was successful in advancing a vaccine injury claim on behalf of their daughter Hannah Poling to the point of settlement by US authorities. Hannah’s father is Dr. Jon Poling, a practicing neurologist in Athens, Georgia, and clinical assistant professor at the Medical College of Georgia. He reviewed his daughter’s case in the Atlanta Journal-Constitution on April 11, 2008. In his comments Dr. Poling explained how mitchondrial dysfunction was related to his daughter’s case and to the existence of a possible mitochondrial dysfunction subgroup of autism disorder. He also discussed, as a medical doctor who expressly recognized the importance of vaccines in preventing serious diseases, the need for public health authorities to abandon fear tactics and conduct research to restore confidence in public health authorities and vaccines

In order to try and staunch the upcoming flood of misunderstandings and false statements like those implied by Doherty (and John Poling whom other mtDNA specialists such as John Shoffner clearly don’t trust on the issue), I contacted Professor Giulivi and asked her three simple questions about the study she is lead author of. She supplied three simple answers.

KL: Do you think, based on available science (including your paper) that vaccines cause autism?

CG: We do not have any evidence for this in our study. Our study was cross-sectional not longitudinal so it cannot point to any cause (not just vaccines), meaning we do not have anydata supporting one way or another.

KL: If so, why is this? Does it follow (in your opinion) that mitochondrial dysfunction can be triggered by a vaccine?

CG: Again, please see (1).

KL: Do you believe your own paper adds weight to any opinion regarding autism causation by any means?

CG: No. At this point we do not know if it is mainly genetic, environmental or a combination of both. Again, with a cross-sectional study you get a snapshot of the situation but not how you got to that situation.

There you have it. The lead author of the study everyone is raving about is very carefully pointing out that the study in question does not add weight to _any_ hypothesis of autism causation, let alone vaccines.

How an autistic brain is re-wired by genes

4 Nov

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, 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.

Social Demographic Change and Autism: part 1

3 Oct

I’ve been meaning to blog this for a long time. Ever since it came online, which was months ago. I’ve wanted to do a good job on this paper and so I’ve kept putting it off while I wait for the time to really dig into it. Kev’s recent post about Prof. Bearman got me thinking it is time to get this out. I knew this would be long and it has grown longer than I expected, so I have split the post up. Here are some introductory thoughts. Much as people like to paint me as being in the “genetics” camp, it isn’t really my interest. Someone like Prometheus would do a far better job on an intro and discussion that I can. But in Prom’s absence, I will say what I can.

Prof. Peter Bearman is a researcher at Columbia University. His team has taken a very careful look at the California Department of Developmental Services (CDDS) data and combined this with California birth record data and come up with what are likely some of the best papers to come from those data. The CDDS provides services to the developmentally disabled in California through a series of “Regional Centers”, which are private corporations which administer the state’s funding through largely non-governmental agencies in the state. They have records on the people (consumers) whom they have served over the years and these data include information on how the consumers qualify for services.

There are five eligibility categories for regional center support:

1) Mental Retardation: Significant deficits in general intellectual functioning (generally an IQ of 70 or below) and significant deficits in adaptive functioning.

2) Cerebral Palsy: A neurological condition occurring from birth or early infancy resulting in an inability to voluntarily control muscular activity, and resulting in significant deficits in motor adaptive functioning and or cognitive abilities.

3) Epilepsy: A disorder of the central nervous system in which the major symptoms are seizures. Eligibility is based on a seizure disorder that is uncontrolled or poorly controlled , despite medical compliance and medical intervention.

4) Autism: A syndrome characterized by impairment in social interaction (withdrawal, failure to engage in interaction with peers or adults), delays in both verbal and nonverbal communication skills, deficits in cognitive skills, and impairment in the ability to engage in make-believe play. Individuals may engage in repetitive activities or a limited repertoire of activities.

5) Fifth Condition: This category includes disabling conditions found to be closely related to mental retardation or requiring treatment similar to that required for individuals with mental retardation.

As a side note, a lot of people forget the “Fifth Condition” category. People will say that people with Asperger Syndrome or PDD-NOS don’t qualify for Regional Center services. Well, they don’t under the “autism” category, but they can under the fifth condition if they meet the requirements for a “substantial disability”. But, I am digressing.

The CDDS data have been extensively used to demonstrate the very large increase in autism prevalence that has occurred over the last 20-30 years.
Prof. Bearman’s group has studied the CDDS data and found that some of the increase can be found to attributed to factors such as changes in the way people are diagnosed (diagnostic accretion) and lower ages of identification.

In a recent paper, Social Demographic Change and Autism, Prof. Bearman’s group argues that about 11% of the rise in autism prevalence can be attributed to genetics.

Sorry to give away the conclusion so early but this is going to be long and I know a lot of people won’t read it all.

Genetics is a hot-button issue with a lot of people in the online autism community. Sometimes people will divide the world into two camps: those who believe autism is caused by vaccines and those who believe autism is caused by genetics. It is a major oversimplification but it happens.

Another oversimplification is to confuse genetics and heritability. As in, “I’m not autistic and my wife isn’t autistic, genetics doesn’t account for my kid being autistic”. This is wrong on so many counts. Heritability implies genetics, but not all genetics is heritable.

In high school or even earlier you probably learned about a monk and pea plants and later studies on fruit flies and the color of their eyes. This is Mendelian inheritance. You learned that some traits are recessive and some are dominant.

From this framework, you can’t get a genetic epidemic.

Whenever the argument about genes and changing prevalence comes up, you can be sure someone will eventually bring up Down Syndrome. Down Syndrome is a developmental disability (possibly an example of the sort that comprise the “fifth category” in the DDS). Down Syndrome is genetic. Not always Mendelian inheritance genetic, but genetic all the same.

The risk factors for having a child with Down Syndrome are

1) Advancing maternal age. A woman’s chances of giving birth to a child with Down syndrome increase with age because older eggs have a greater risk of improper chromosome division. By age 35, a woman’s risk of conceiving a child with Down syndrome is 1 in 400. By age 45, the risk is 1 in 35. However, most children with Down syndrome are actually born to women under age 35 because younger women have far more babies.
2) Having had one child with Down syndrome. Typically, a woman who has one child with Down syndrome has about a 1 percent chance of having another child with Down syndrome.
3) Being carriers of the genetic translocation for Down syndrome. Both men and women can pass the genetic translocation for Down syndrome on to their children.

Part 2 and 3 are what we usually think of as “genetic”, as in “Mendalian”. But what about (1) advancing maternal age? A 10 times greater risk for older mothers? Keep in mind, there is a clear genetic difference behind Down Syndrome.

In humans, the egg cells and sperm cells have 23 chromosomes. The rest of your cells normally contain 23 pairs of chromosomes — one from your father and one from your mother. Kids with Down syndrome usually have three copies of chromosome 21 — called trisomy 21 — instead of two copies.

There is a difference, some might call it an error, in the genetic sequence which leads to Down Syndrome. The parents don’t need to have it. It can be genetic and not heritable. Or, at least, not heritable in the way most people think.

Parental age is increasing. We would be seeing an epidemic of Down Syndrome if it weren’t for the genetic test that is available and offered to most pregnant women.

There are already studies out discussing increased risk for having an autistic child with parental age. If parental age is increasing (and it is), why don’t we see an epidemic of autism from this?

Add to this the recent study from the Autism Genome Project (which came out after this paper by Prof. Bearman’s group). That study, and others, are showing that rather than an autism “gene”, that copy number variations (CNVs) may be one source of genetic risk for autism. These are not heritable in the usual sense as usually they exist in the child and not the parent.

According to Prof. Bearman, we are seeing it. It accounts for about 11% of the increase in autism prevalence in the CDDS data. It is a big effect, but small compared to the other factors going on (the other 89%). So without a careful look, one can’t show it.

Prof. Bearman’s group *is* taking a careful look. The result is their paper Social Demographic Change and Autism. There are a lot of very interesting results, like twin concordance being much smaller than has been previously reported. Another recent paper confirms that. Strangely, no one seems to have noticed.

I’ll try to rectify that in the next installment when we look closer at the paper. Until then, here is the abstract:

Parental age at child’s birth—which has increased for U.S. children in the 1992-2000 birth cohorts—is strongly associated with an increased risk of autism. By turning a social demographic lens on the historical patterning of concordance among twin pairs, we identify a central mechanism for this association: de novo mutations, which are deletions, insertions, and duplications of DNA in the germ cells that are not present in the parents’ DNA. Along the way, we show that a demographic eye on the rising prevalence of autism leads to three major discoveries. First, the estimated heritability of autism has been dramatically overstated. Second, heritability estimates can change over remarkably short periods of time because of increases in germ cell mutations. Third, social demographic change can yield genetic changes that, at the population level, combine to contribute to the increased prevalence of autism

Why are autistic people mainly male?

17 Sep

Excluding the ever humorous ideas of the Geier’s and more serious ideas of Simon Baron-Cohen regarding testosterone, the reasons as to why there are (or seem to be) many more autistic males than females have not been adequately explained. However that might be about to change.

A new study gives the first starting point as to why this situation might come about.

As we all know, males have an X and a Y chromosome whereas females have two X’s. This new study postulatesthat this fact plays an important role.

If a boy’s X-chromosome is missing the PTCHD1 gene or other nearby DNA sequences, they will be at high risk of developing ASD or intellectual disability. Girls are different in that, even if they are missing one PTCHD1 gene, by nature they always carry a second X-chromosome, shielding them from ASD…

The PTCHD1 gene is responsible for determining the development of human embryo’s and is already associated with autism. Because males only have 1 X chromosome, if this is defective then they – obviously – don’t carry that secondary level of shielding that females – with 2 X chromosomes – do.

However, this is very much preliminary. It should be noted that:

The researchers found that about one percent of boys with ASD had mutations in the patched domain containing 1 (PTCHD1) gene on the X-chromosome.

1% is not a very high number but as LBRB interviewee Stephen Scherer says:

The male gender bias in autism has intrigued us for years and now we have an indicator that starts to explain why this may be…

In other words, no one is saying this is a done deal – merely that its a strong possibility with some decent science behind it.

Misfolding neural proteins

14 Sep

Regular readers might recall me blogging about neural proteins awhile ago. If I may quote myself:

…when the authors blocked APC function, they found that levels of the proteins neuroligin and neurexin dropped. So what…? Well, without these two proteins at normal levels, synapses grew improperly. So what…? Turns out that scientists already know that mutuations in the genes for neuroligin and neurexin are associated with autism…

And now along comes a new study that builds on this science.

Palmer Taylor, associate vice-chancellor for Health Sciences at UC San Diego and dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences, and colleagues report that misfolding of a protein called neuroligin-3, due to gene mutations, results in trafficking deficiencies that may lead to abnormal communications between neurons.


So here we have a situation where genetic mutations leads to a misfolding of a protein that results in affecting the growth of synapses which in turn affects the development of autism.

Taylor said identifying and describing the misfolded protein link advances understanding of the complex causes of certain autisms, including the influences of genes versus environment…

Thats an interesting statement. I will try to get in touch with Taylor to explain that further.

Quick Q&A with APC study lead author

26 Aug

I recently blogged about a study that linked APC dysfunction with autism and learning disability. Two questions interested me so I wrote to lead author Michele Jacob to ask them.

Hi Dr Jacob,

My name is Kevin Leitch, I own and edit a popular blog on autism and am also father to an autistic daughter.

I found your recent study very interesting and had questions that I’d like to ask you and hopefully you’d give me permission to discuss your answer on the blog?

My questions are –

1) is there any set of circumstance in which APC dysfunction can occur ‘in the wild’ e.g. could a child be given something that then ‘turned’ them into an autistic person by negatively affecting APC function?

2) If there *is* , is there a way that this dysfunction might be reversed or at least modified somewhat?

My own take on this is that the answer to both questions would be ‘no’ but I have no understanding of APC function and a laymans understanding of genes in general.

Many thanks in advance for both your fascinating study and any time you can offer me in answering my questions.

She responded:

Hi Kevin,

Thanks for discussing our work in your blog. I am delighted our work interests you.

I think the short answer to both questions is no. The only way to cause APC dysfunction is via gene mutations. It’s function can be modified, enhanced or reduced, by signaling events in cells, but these changes are not large enough to have effects on behavior.

Loss of function mutations in the APC gene are inherited or occur sporadically. The symptoms associated with the sporadic mutations will depend on the cell type. APC is present in all cells of the body and it has several functions that are critical at different stages of development.

My lab is continuing to define the role of APC in the nervous system. Our goal is to define changes caused by APC dysfunction that lead to learning deficits and autistic-like behaviors.

Hope this information clears up your questions.

My best regards to you and your daughter.

So why did I ask these questions? Well, its been my experience that the antivax crowd leap on any science that seems to have an outcome that is linked to autism, to either trash it or link vaccines to it. I’m hoping Dr Jacob’s answers lead away from the possibility of linking autism to vaccines via APC dysfunction.

Autism and learning disabilities connected to APC protein

25 Aug

‘What the hell does that mean?’ I hear you cry.

OK, so the way I understand it, APC is a protien which plays an important role in helping synapses grow properly. If synapses – which are the bits that transfer data from neuron to neuron – don’t grow properly then data doesn’t get passed properly. This particular protien – APC – is responsible for the synapse function for learning and memory.

In the in vivo study, the team blocked APC function and found that synaptic levels of the cell adhesion proteins neuroligin and neurexin dropped considerably. Without normal levels of these proteins, synapses were less mature both structurally and functionally. Mutations in the genes for neuroligin and neurexin are associated with autism in humans, but until now, little was known about the mechanisms responsible for localizing these proteins at the synapse. “Our laboratory study is the first to show that APC is needed to recruit neuroligin and neurexin to the synapse. This finding provides new insights into the mechanisms required for proper synapse function as well as molecular changes at the synapse that likely contribute to autistic behaviors and learning deficits in people with APC loss of function gene mutations,” said [lead author, Michele H. ] Jacob.

Source. Insert mine.

Right, so – again as I understand it – when the authors blocked APC function, they found that levels of the proteins neuroligin and neurexin dropped. So what…? Well, without these two proteins at normal levels, synapses grew improperly. So what…? Turns out that scientists already know that mutuations in the genes for neuroligin and neurexin are associated with autism. Aha.

Functional impact of global rare copy number variation in autism spectrum disorders

14 Jun

A recent study by the autism genome project has been gathering a lot of publicity. Kev interviewed one of the principle investigators. But, we haven’t really presented a discussion of the science here. With that introduction, you might be surprised to read: and that isn’t going to change. A few good presentations have been written on this paper. Far better presentations than I can do. So I will refer you to:

The Simons Foundation SFARI blog has Autism marked by copy number changes in coding regions. (note: I added this link after the initial publication of this blog post)

P.Z. Myers in Autism and the search for simple, direct answers and Respectful Insolence with, More evidence for a genetic basis for autism.

The paper itself is Functional impact of global rare copy number variation in autism spectrum disorders, appears in the journal Nature.

Here is the abstract:

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4?×?10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Autism and mental retardation – genetic overlap

30 May

Post taken from Medical News Today

Researchers working with Professor Gudrun Rappold, Director of the Department of Molecular Human Genetics at Heidelberg University Hospital, have discovered previously unknown mutations in autistic and mentally impaired patients in what is known as the SHANK2 gene, a gene that is partially responsible for linking nerve cells. However, a single gene mutation is not always enough to trigger the illness. In some cases, a certain threshold of mutation must be exceeded. The researchers conclude from their results that a correct inner structure of the nerve cell synapses is necessary to enable the normal development of language, social competence, and cognitive capacity. Essential for the success of the project were the studies by the Heidelberg research team with the doctoral student Simone Berkel and collaboration with a Canadian research team headed by Steve Scherer. The study has already been published online in the leading scientific journal Nature Genetics.

Autism is a congenital perception and information-processing disorder of the brain that is often associated with low intelligence, but also with above-average intelligence. The disease is characterized by limited social communication and stereotypical or ritualized behavior. Men are affected much more frequently than women. Autism and mental retardation can occur together but also independently of one another and are determined to a great extent by hereditary factors. Some of the responsible genes have already been identified but the precise genetic mechanisms have not yet been explained.

Genetic makeup of hundreds of patients analyzed

Professor Rappold and her team focused their studies on the SHANK2 gene, which encodes a structural protein at the nerve cell synapses. It is responsible for the mesh structure of the basic substance in the postsynapse. Only when the postsynapse is properly structured can nerve impulses be correctly transmitted. The researchers analyzed the genetic material of a total of 396 patients with autism and 184 patients with mental retardation. They found different mutations in their SHANK2 genes in the area of individual base pairs, but also variants in the number of gene copies. The mutations led to varying degrees of symptoms. None of the observed gene variants occurred in healthy control persons. “Apparently an intact postsynaptic structure is especially important for the development of cognitive functions, language, and social competence,” explained Professor Rappold.

Identical mutations as the cause of different diseases

Some of the genetic mutations identified were new occurrences of mutations that were not inherited from the parents, but some of the mutations were also found in one parent. Since there are also healthy carriers of gene variants, we must assume that a certain threshold of gene mutations must be exceeded for the disease to appear. “Moreover, the same mutation can be present in an autistic patient with normal intelligence and in a mentally impaired patient,” said Professor Rappold. There is some overlap in the clinical symptoms of mental retardation and autism, which can now be explained by a common genetic cause.