Important New New Research Article on Autism Genetic Marker

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A research paper was just published last week that identifies 237 different genes that can be used to identify if an individual is diagnosed as Autistic or would be a Neurotypical. In my opinion this is one of the most significant genetic research articles on autism I have seen.

Preceding the abstract I define the term Single Nucleotide Polymorphism and give an example of a biochemical pathway. (I am not the best writer and struggled all my life with writing clear organized paragraphs. Hopefully I have done an adequate job here.) I have simplified the definitions and terminology so they are substantially accurate in general but a biologist would take exception to some of my word usage. My purpose is to make this information available to as many people as possible without requiring them to take a course in genetics. I have also edited the article's abstract to remove scientific jargon and make it more understandable to a non-scientific audience. I bracketed any terms I either added or changed from the original. An ellipse (...) indicates where I deleted material from the original.

Scientifically minded readers can go directly to the link at the bottom of the post.

Term defined:
SNP = Single Nucleotide Polymorphism. Genes are sequences of DNA that code for proteins. A gene occupies a specific place on a chromosome and consists of a stretch of DNA with a beginning and an end. For any given gene there are usually polymorphisms. This means that in a population a gene has more then one form. For example we all know that many different forms of the gene for eye color exist in human populations: brown, blue, green etc. The eye color gene is polymorphic in the human population. Or to say it a different way: more than one DNA sequence of the eye color gene exists in the human population. If there is only one spot (a nucleotide) in the DNA sequence that is different among the forms of a gene in a population it is called a single nucleotide polymorphism. This means there is only one coding point of DNA in the gene form that is different from the other forms. In general this means that when a gene is expressed in individuals with different forms of a gene each will have a slightly different protein in one of the biochemical pathways in their body.

Many processes in our body have very complex biochemical pathways. For example when a human body produces estrogen or testosterone, the process starts with cholesterol and goes through many intermediate molecules before it gets to its final form. Each step in the biochemical pathway is catalyzed (facilitated) by a protein enzyme that is coded by a unique stretch of DNA called a gene:

Cholesterol --> Intermediate A--> Intermediate B --> Intermediate C --> Intermediate D --> etc --> Estrogen or Testosterone. (As an aside these two hormones have very similar molecular structure.)

Abstract

"[The diagnosis of] Autism spectrum disorder depends on a clinical interview [because there are no known genetic markers] to aid [in the] diagnosis. [This research study looks at] single-nucleotide polymorphisms (SNPs) of individuals with Autism Spectrum Disorder. [The] SNPs [we looked at] were mapped to ...[biochemical] pathways [that] identify [specific] cellular processes [in individuals with Autism Spectrum Disorder]....

We created a genetic diagnostic [system] consisting of 237 SNPs in 146 genes that correctly predicted Autism Spectrum Disorder diagnosis in 85.6% [individuals] of Central European [ancestry] .... [There were] eight SNPs in [particular]... [that] had the largest effect... with some [SNPs] acting [to make an individual more likely to have Autism Spectrum Disorder], whereas others were protective [individuals having this SNP were more likely to be Neurotypical]....[Using a smaller subset of SNPs] our diagnostic [system] correctly predicted Autism Spectrum Disorder diagnosis with an accuracy of 71.7% in [individuals] of Central European [ancestry].

In conclusion, we have developed an accurate diagnostic test for a [specific human population]...[and this]... approach identified cellular processes common to Autism Spectrum Disorder across ethnicities."

http://www.nature.com/mp/journal/vaop/n ... 2126a.html

I just found this article today and have not had time to fully investigate the specific biochemical pathways involved in autism. I hope to do this in the future and present my results in a future post.

Great explanation and great find Pompei, thanks for posting this. You obviously know much more about this stuff than I do so maybe you can answer this question for me. The test subjects were central european and to me the article seemed to suggest that they had a generally uniform ancestry. It also suggested that this specific test may not be accurate for say Mongolian people but it could be possible to create a test for Mongolians because the genetics of the population are generally uniform. Would it be possible to apply this to a very diverse population like in the US where many people are of mixed race to the point where many don't even know their racial makeup? Am I understanding this right?

Now I'm really scared.

Nice. Science is really awesome.

I have put together a summary of the paper eliminating most of the scientific jargon while keeping the main data and inserting a few comments. I believe this will answer your question.

The researchers first assigned ethnicity to individual samples by comparing SNPs and grouping them to their closest ethnicity. Individuals of mixed ethnicity were excluded.

There were 3 groups:
Central European or Utah USA ancestry,
Tuscan Italian ancestry and
Hans Chinese ancestry.

Only 627 SNPs were different between the Tuscan Italian ancestry and the Central European/Utah ancestry groups. This shows there was no significant differences between SNPs in these two ancestry groups. However there were 116,753 different SNPs between the Central European/Utah ASD group and Han Chinese ASD group indicating these two populations differ significantly in SNPs.

The researchers next proceeded to only analyze and create a test specific to the Central European/Utah group.
For each individual of Central European/Utah ancestry 775-SNPs were examined to see if they could predict an individual’s clinical status (ASD versus non-ASD). From the 775 SNPs identified within the Central European/Utah ancestry group, an accurate genetic classification of ASD versus non-ASD was possible using 237 SNPs in 127 different genes determined to be highly significant.

Using the 237 SNPs in 127 genes comprising 13 biochemical pathways from the Central European/Utah analysis the researchers tried to identify ASD individuals in the following three test groups.

Three cohorts were used for validation:
1. 243 diagnosed ASDs and 42 controls of Central European/Utah ancestry;
2. 65 ASD and 88 controls of Tuscan Italian ancestry;
3. 33 ASDs and 169 controls of Han Chinese ancestry.

Classification accuracy for the 285 Central European/Utah ancestry validation cohort was 85.6% and 84.3% for the Tuscan Italian while accuracy for the Han Chinese cohort was only 56.4%.

The researchers looked at the biochemical pathways comprising the ASD SNPs for both Central European/Utah groups and the Han Chinese groups. They discovered the Hans Chinese ASD groups and the Central European/Utah ASD groups have different biochemical pathways that identify their ASD individuals. The researchers identified 13 ASD biochemical pathways in the Central European/Utah group and 16 ASD biochemical pathways in the Hans Chinese group but only six of these biochemical processes were common across both ethnic groups. Because of this disparity the genetic tests these researches created could not identify the Hans Chinese ASDs using the data they compiled from the Central European/Utah group. Their test was sub-optimal predicting only 56.4% of the Hans Chinese ASDs,, only slightly better than chance. It is likely that an additional set of SNPs may be predictive of an ASD diagnosis in Han Chinese and that methods used for developing the Central European/Uta test could be applicable to other ethnicities.

Nevertheless it is very important that six common pathways were identified across all ethnicities and further research can be expected to generate data to allow identification of ASDs in Hans Chinese populations. These researchers did not pursue that line of investigation in this paper. While the researchers did not address the question of mixed raced individuals, future research in my opinion will generate results to make this distinction.

A very important finding in this paper is that Eight SNPs in three genes, GRM5, GNAO1 and KCNMB4 were highly indicative of ASD status. The biochemical functions of these genes correspond to the ASD neuroanatomical differences that have been reported in many other scientific papers.

The KCNMB4 gene is a potassium channel that is important in neuronal excitability and has been implicated in epilepsy and dyskinesia. It is highly expressed within the fusiform gyrus, as well as in superior temporal, cingulate and orbitofrontal regions http://human.brain-map.org/ which are areas implicated in face identification and emotion face processing deficits seen in ASD.

The GNAO1 gene codes for a protein that is a subgroup of a G-protein that couples with many neurotransmitter receptors. Mice with the GNAO1 knocked out exhibit ‘autism-like’ features, including impaired social interaction, poor motor skills, anxiety and stereotypic turning behavior. GNAO1 has also been shown to have a role in nervous development at neuronal dendrites and synapses, and interacting with the GAP-43 gene at neuronal growth cones, with increased levels of GAP-43 demonstrated in the white matter adjacent to the anterior cingulate cortex in brains from ASD patients.

Different GRM5 SNPs have either an ASD contributory or a protective effect. the GRM5 gene is highly expressed in hippocampus, inferior temporal gyrus, inferior frontal gyrus and putamen regions implicated in ASD brain MRI studies. GRM5 has a role in synaptic plasticity, modulation of synaptic excitation, innate immune function and microglial activation. GRM5-effedts include stereotypies, sensory motor gating deficits and deficits in working, spatial and recognition memory. features described in ASD. With regard to GRM5’s involvement with neuroimmune function, this receptor is expressed on microglia with microglial activation demonstrated by us and others in frontal cortex in ASD. (From Wikipedia: [microglial cells play a] supportive role to neurons...They are mobile within the brain and multiply when the brain is damaged. In the healthy central nervous system, microglia processes constantly sample all aspects of their environment (neurons, macroglia and blood vessels).) Further GRM5 may contribute to glutamatergic dysregulation in ASD. (From Wikipedia: "Glutamate receptors... [have a] central role in the central nervous system..These glutamate receptors...neurotransmitter[s], [are] the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation. [They] are suggested to play a role in modulating gene expression in glial cells....mice... [with] abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. ")

Last edited by Pompei on 24 Sep 2012, 2:53 pm, edited 5 times in total.

Likewise.

Why be scared. When you cut through all the details what I see is that scientists need to look at hundreds of genes in order to identify someone on the spectrum. In this article they needed to look at 127 genes and only came up with an accuracy rate of 85%. If a woman went to the doctor and the doctor told her she had an 85% chance she was pregnant how satisfied would she be with that result? I interpret this to mean that there are hundreds if not thousands of genes that affect whether someone is or is not on the spectrum. All of this variation in the population persists even though some of the effects are deleterious. Evolution by natural selection works by eliminating deleterious genes so it is highly probable that most of the genes have some kind of beneficial effect. I am greatly encouraged by this. It means autism is not some simple condition that is the result of a simple mutation but rather that the genes for being on the spectrum are like genes for tallness, that is to say it is quantitative and polygenic. Autism is the result of many genes interacting with each other in a very complex way. It explains why we are so different from each other while we share many common traits. There is yet a huge amount to be learned but I consider this to be strong evidence that the neurodiversity movement is correct and we aspies and auties are not deficient but just different.

A Genetic Theory of Neurodiversity

Thesis:
The implication of so many genes successfully interacting among a great variety of biochemical pathways suggests there exists a yet undiscovered "master regulatory element" within the human genome. This regulatory element coordinates and controls the development of the abundant autistic genetic material in the DNA of a small percentage of developing fetuses and organizes the integration of the numerous autistic biochemical pathways to produce a healthy holistic human phenotype called an Autistic. This Autistic human has a highly desirable well functioning brain with unique inter-connectivity that functions differently from NT brains and facilitates the development of unique and valuable talents and abilities lacking in neurotypical brain circuitry.

Autism is not caused by the random accumulation of a bunch of genes with deleterious effects. Autism is not a dysfunctional mistake. This erroneous conclusion does not make sense because it would mean Autistics carry a massive genetic load comprising hundreds of bad genes with cumulative deleterious effects. Such a brain with dozens of dysfunctional biochemical pathways would be so poorly organized and low functioning as to likely be lethal or to burden its possessors with mental handicaps so enormous they would be catatonic. I argue instead that just as autism has a spectrum with handicapped persons at one end and brilliant geniuses at the other so do NTs. NTs could be organized on a spectrum with geniuses at one end and highly disabled, dysfunctional and handicapped persons on the other. Autistics and NTs are in truth two different types of humans each with its own unique brain chemistry. We possibly see some intermediates between Autistics and NTs populated by technically capable individuals like NT engineers and NT chemists that share some traits of both NT and Autistic behaviors. However, it is also possible, given the great difference in the two types of brain circuitry between NT and Autistic brains, that it is the intermediate phenotypes who are the most severely handicapped "Autistics" since they would lack either the NT or the Autistic regulatory organizing mechanism that insures the integrity of brain circuitry whether it comprise Autistic or NT brain cellular function.

In other words Something within our genetic system organizes all of the genetic elements that make up autism and give it a well designed healthy cohesive structure with integrity. It is why Evolution produces Einsteins, Beethovens,,Mozarts, etc. Autistic geniuses are not the result of hundreds of dysfunctional biochemical pathways comprised of bad genetic material that just happen to combine to produce an occasional eccentric genius. That makes no sense. Evolution by natural selection produces among millions of humans a few unique NTs and a few unique Autistics who are highly successful and amazingly talented individuals.

Evolution has also not eliminated the numerous autistic genes because they are not bad genes. They remain in the gene pool because they have beneficial effects.

Hmm that is pretty close to what I've thought for a while......that its a bunch of interactions between various genes, not something simple that can be removed or 'fixed'.

I thought that the article was related to genetic prenatal testing and that's why I was scared. I feel that all babies should be brought into this world and parents shouldn't be playing God, deciding which of their children will be born and which of them will be aborted. I'm against genetic screening of any kind and I'm pretty sure it wouldn't exist if the Holocaust didn't happen.

Well I am glad you understand it was not about testing a fetus. There are several data bases of genetic information that scientists use to do basic research. Right now we don't know enough about autism genetics to develop a prenatal test but i suppose it is inevitable that the medical profession will develop one. The research journal articles are usually several years ahead of the development of any practical uses for their results. I share your concern about the potential abortion of a fetus because it has autistic genetic markers and hope that we come to understand autism well enough that a pregnant mother would not choose to get an abortion because her baby might be autistic. On the other hand testing a newborn and knowing it had autistic genetic markers would be helpful to parents so they could identify the differences and make adjustments in child rearing for its benefit.

What if it turns out there are many people in our society who appear completely neurotypical and don't have any of the downsides of Asperger's or autism ... and yet have the genetic markers? Is it possible that for some people the aspie thing is an advantage that helps them get ahead, and they have no idea that's why? Sounds like a lot more research needs to be done ...

You are correct. It is entirely possible that there exist aspie genes which make an individual more likely to possess the positive elements of autism but lacking those that are less than welcome. There are many possible explanations for the existing data. While I have confidence my analysis of the research accurately reflects the content of the paper I described, my theory is just a proposal for consideration. It is a completely speculative theoretical hypothesis without any evidence to support it.

I have proposed a dualism because the physiological and neurological data show autistic brains are greatly different in their morphology from NT brains. Moreover they are all similar in morphology to each other and yet we know there is great diversity among us. Scientists know autistics are born with their unique brain circuitry It also makes sense to me that there is some mechanism that coordinates the developmental processes of autistic neurodevelopment. There have been many speculative ideas suggesting autism is the result of some environmental insult like too much testosterone in the womb, a pathogen or a toxin. I personally do not find these theories credible. I wanted to create an alternative explanation that leaves out all of the pathology but I have no evidence my explanation has any validity. I do however believe it is plausible. I just get so tired of reading about all the horrible dysfunctionality described in nearly all autism research.

Eugenics didn't start in Germany. Hitler got the idea from England and America, and it stretched out as far as Australia.
It existed before the Holocaust.

You don't think other theories are credible, but you have no evidence to support your own theory, or its meaning. If you leave out pathology, your theory won't explain much.

I agree that environmental insults have little if any credibility as a monocausal explanation for autism, but given the number of genes that appear to be involved, could it perhaps be that these insults work on an epigenetic level and activate (or deactivate) gene sequences?

Thanks for the post btw. Haven't had the time to study it in detail yet, but I will.