News The latest developments in autism research.

Postmortem brains point to molecular signature of autism

by  /  22 December 2014

Immune link: Brain tissue samples from people with autism show increased expression of genes involved in immune responses.

An analysis of genes expressed in the postmortem brains of people with autism has identified three molecular pathways linked to the disorder. The findings, published 10 December in Nature Communications, add to mounting evidence that the myriad causes of autism converge on common biological processes1.

“Each of these individuals probably has autism for a very different reason, yet you do see a very clear commonality,” says Dan Arking, associate professor of genetic medicine at Johns Hopkins University in Baltimore, Maryland, and one of the study’s lead investigators.

The researchers sequenced RNA in postmortem brain tissue samples from 32 people with autism and 40 controls between the ages of 2 and 82. The samples came from the brains’ outer layer, called the cortex, which plays a role in language and social skills. These are often impaired in autism.

The brains of people with autism show higher expression of genes involved in immune responses than do the brains of controls. They also show changes in the expression of some genes that play a role in signaling.

The findings fit with those of a smaller study published in 2011, which looked at gene expression patterns in the postmortem brains of 19 people with autism and 17 controls2. That study found that people with autism show increased expression of genes involved in immune responses, and diminished expression of genes that function at synapses, the junctions between neurons.

“Given that gene expression is known to be very variable, the fact that this molecular signature of autism observed in autism brains is robust across distinct methods and cohorts is a very important result,” says Irina Voineagu, senior lecturer of biological sciences at the University of New South Wales in Sydney, Australia. Voineagu was involved in the 2011 study but not the new work.

Revealing networks:

Like the older study, the new research focuses on networks of genes, called modules, that show a similar pattern of expression across brains. Each module comprises genes that characterize a particular cell type or are involved in the same function, such as communication between neurons. Arking and his colleagues identified 12 modules, 3 of which are expressed at different levels in the brains of people with autism than in controls.

The module that shows the greatest activation in people with autism, known as mod5, contains 759 genes. Many of these genes are related to activated microglia — immune cells in the brain that become activated in response to injuries and infections. These cells also help to shape synapses.

The study also identified three distinct modules, mod6, mod1 and mod2, that contain genes expressed predominantly in neurons and involved in signaling.

The 667 genes in mod6 are slightly more active, on average, in people with autism than in controls. By contrast, mod1 genes show decreased expression overall in people with autism. Mod1 holds 1,646 genes linked to signaling by gamma-aminobutyric acid (GABA), a chemical messenger that inhibits brain activity.

The researchers found a strong link between the dampening of mod1 and the activation of mod5 in people with autism. This suggests that microglia activation and neuronal dysfunction may go hand-in-hand, Arking says.

The third module, mod2, which contains 1,319 genes, is the only one enriched with autism candidate genes, including ADNP, ANK2, DSCAM and GRIN2B. Neither the module overall, nor any of the known candidate genes, differ in expression between people with autism and controls.

This comes as a surprise to Valerie Hu, professor of biochemistry and molecular biology at George Washington University in Washington, D.C. Hu was not involved in the new work, but has done several gene expression studies, including some comparing the gene expression profiles of blood cells from people with autism and controls. “We definitely see overlap between [autism candidate] genes and our differentially expressed genes,” she says.

Study co-leader Andrew West was less surprised. “There might be hundreds or even a thousand genes linked to autism,” says West, associate professor of neurology and neurobiology at the University of Alabama at Birmingham. “But that we would see each one in every brain deregulated in some type of common way, I don’t think aligns with the heterogeneity of the disease.”

Common pathway:

Overall, the findings align well with those from the 2011 study. Both studies point to an enhancement of immune pathways and a dampening of neuronal signaling in the brains of people with autism.

However, whereas the older study linked the immune pathways to both activated microglia and star-shaped cells called astrocytes, the new work fingers only microglia. “We have a larger sample size, which allows us to narrow down the relevant genes that are involved,” Arking says.

The new study suggests that autism-linked mutations tend to strike genes involved in neurons’ functions. By contrast, the activation of microglia-related genes appears to be unrelated to mutations.

However, it is too early to say how neuronal dysfunction and microglia activation are related, if at all. “Are microglia responding to alterations in neuronal or synaptic function? Or could they be playing a more early and direct role in driving some of that dysfunction?” says Beth Stevens, assistant professor of neurology at Boston Children’s Hospital, who was not involved in the study. “I think that question is still out there.”

The findings fit with those from an imaging study published last year, which found that microglia are more activated in people with autism than in controls. It is still unclear whether microglia activation is helpful or harmful in the brains of people with autism. “This study raises a lot of important questions for us in the field to try to understand,” Stevens says.

The study also suggests that the many causes of autism act through common pathways, which may one day serve as targets for therapy.

“I thought it was a high possibility that autism is so heterogeneous that we wouldn’t identify any particular process that seems to be conserved,” West says. “The fact that we do gives a lot of hope that you can find a targeted and rationally derived approach to alter these states.”


1. Gupta S. et al. Nat. Commun. 5, 5748(2014) PubMed

2. Voineagu I. et al. Nature 474, 380-384 (2011) PubMed

11 responses to “Postmortem brains point to molecular signature of autism”

  1. concerned autism parent says:

    “The brains of people with autism show higher expression of genes involved in immune responses than do the brains of controls.”

    This is evidence that our kids are genetic over responders so maybe, just maybe, the logical, sane thing to do is to not overload babies immune systems with multiple shots since some children, as this analysis shows, are genetically more immune sensitive/ prone to adverse reaction. Vaccines are designed to provoke an immune response which in this subset of children can be very risky. We should protect these children which means screening them prior to vaccinating.

  2. DS says:

    I whole heartedly agree with “concerned autism parent”. This has direct ramifications for the timing of and amount of immunizations this subset should receive which definitely means screening prior to vaccinating is required.

    • bjauregui says:

      I can see how you can get to the conclusion that vaccines might have something to do with autism given that this study talks about immune activation responses in people with ASD. But there is a huge amount of evidence out there that has proven over and over again that vaccinated children are NOT more likely to have autism compared to unvaccinated children. The hypothesis of vaccines causing autism has already been proven wrong in countless studies.. I’m the aunt of a boy with autism and I have read all about it. Science will hopefully find an answer soon, possibly by reducing gene expression as this article says.

  3. Judi says:

    Can someone please explain how this latest finding might relate to fever-induced reduction of certain asd core symptoms. There is much anecdotal evidence to support this, including my own observations that consistently reveals this to be true with my grandchild; whenever his language is unusually coherent and his social interactions increase, there is always a fever involved.

    • jorge says:

      There is some research that was done by increasing the core temperature in ASD children and obseved improved performance. This research can be viewed at the Autismone video section. I don’t recall the name of the authors.

  4. Kadi Luchsinger says:

    Let me first say that what you all are doing is phenomenal but as I speak out as a non profit who works diligently to promote brain donations with our members – the picture you posted is so disrespectful. I think the study is great and appreciate the hard work of all involved, however, the picture is one that offends many parents of families who donated brain tissue.

  5. Steve White says:

    I kind of agree with Kadi Luchsinger above. I know a lot of neurologists, doctors and researchers read this but with the parent contingent, maybe best to avoid this kind of thing. And on that topic many thanks to people who helped with donations.
    About the paper and article contents — this is something they’ve been talking about for years, so it’s not a surprise, but my question is, will this actually help treatment/prevention? If you’ve got 100 genes involved in synapse formation (just making this up as an example) then you’ve still got to find the 100 genes and see if any are impaired, you don’t get to look at someone’s brain after their autism diagnosis and then see faulty synapses and fix them later. So, crucial to understanding brain development but may or may not have medical value.

    • Seth Bittker says:

      This is an excellent point Steve. This paper does nothing from a treatment / prevention perspective. In addition to the 100s of genes involved in synapse formation one might also consider the 100s of genes that are involved with the immune system as well. This in itself is simplistic as gene expression is very much a function of the environment. So even if genetics is “loading the gun”, it would make a lot of sense to look at the environment to attempt to ameliorate its affects.
      Unfortunately the “genetics first” bandwagon seems to be becoming enshrined as the way forward on autism research. I wish we could stop it. Instead we should be looking at biochemistry and what environment factors are upregulating immune response and as importantly what factors could downregulate it.
      It is my opinion that it will eventually be found that one factor that is fundamental to upregulating immune response (and a contributing factor in inducing autism in many) is oral vitamin D and specifically the vitamin D drops that are given to infants in the modern world.

  6. usethebrainsgodgiveyou says:

    “The module that shows the greatest activation in people with autism, known as mod5, contains 759 genes. Many of these genes are related to activated microglia — immune cells in the brain that become activated in response to injuries and infections.”

    That’s pretty interesting. Rubella infection was said to have increased the odds of autism 200 fold. Thalidomide, too, was injurious. Cerebellar injury AT BIRTH has been said to increase rates of autism 36 fold, only monozygotic twins have a higher correlation.

    It seems a vulnerability, however, could lead to autism before the environmental injury or infection occured. Half of children who developed an HHE response to vaccine followed in a long term (the only long term study) in 1979 were predisposed genetically to autism or other neurological disease. To say the injury or infection caused the autism is not necessarily true. Perhaps the vulnerability that caused the autism, also caused a vulnerability to infection/injury.

    Regardless…this is just a tiny step.There are still far more questions than answers.

    • Ethyl says:

      The immune pathways —yes. We know this from the past. But is it a viral insult early in pregnancy that causes the disruption? Or perhaps a lack of essential nutrients?

      The Zika virus causes a disruption in typical maturation of the fetus in pregnant women who contact it. It is so similar, phenotypically (?), to the microcephally caused by iodine deficiency. It is new enough I don’t know that it causes autism, as iodine deficiency does.

      It’s a miracle any of us avoid all the pitfalls that nature throws at us.

  7. Yet to be Diagnosed Adult says:

    Am I the only one who doesn’t want to be the first to have my “state” altered? Especially since it looks like they’re about to serve up the brain specimens like tostadas at a party. No, seriously, the way they talk about RNA expressing itself reminds me more and more of music. The available notes are all there that can be played, discovering what they are has been useful. Then they realized that there’d never be any reason to play/express all those notes all at the same time. Which seems obvious now, but wasn’t always. Here, now, they have identified one particular song’s form. That structure too may remain rigidly the same as the scale from which it is derived. But what I have yet to see is some accounting for how the way it is performed can vary so drastically from singer to singer and performance to performance.

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