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Julia Yellow
News

Gene expression patterns may underlie autism’s gender bias

by  /  5 May 2016

Genes that are expressed at higher levels in men’s brains than in women’s also tend to be enriched in the brains of people with autism. Many of these genes are markers for immune cells called microglia, which have been implicated in autism.

If elevated expression of these genes raises the risk of autism, the findings may help explain the skewed sex ratio in the condition, says lead investigator Daniel Geschwind, distinguished professor of neurology, psychiatry and human genetics at the University of California, Los Angeles. The results appeared 19 February in Nature Communications1.

The sex bias in autism is among the most-studied but least-understood aspects of the condition. Some researchers suspect that many girls with autism may go undiagnosed, either because they have subtler symptoms than boys do or because existing diagnostic tests preferentially detect boys. But others have found evidence that girls need more genetic mutations than boys do to reach the threshold for an autism diagnosis.

The new study adds to mounting support for the idea that autism’s sex bias is at least partly rooted in genetics.

“This study makes it very likely that at least some of the difference in prevalence between males and females is biological and not just about lack of recognition,” says Lauren Weiss, associate professor of psychiatry at the University of California, San Francisco, who was not involved in the work.

Intriguingly, none of the gene sets strongly linked to autism risk so far show a significant sex bias in their expression levels.

“I think what we have to do now is hunt down the link between [autism] risk genes and these genes that are differentially expressed between the sexes,” says Thomas Frazier, director of research at the Cleveland Clinic’s Center for Autism in Ohio, who is not connected to the study.

Looking for overlap:

Geschwind’s team used BrainSpan, a repository of gene expression data from postmortem brain tissue, to identify genes that are expressed differently in men and women. They focused on data from the brain’s outer layer, called the cerebral cortex, in five males and five females with no known neurological conditions. They identified 866 genes that show variable expression between the sexes.

They then looked for any overlap between these genes and four existing lists of autism-linked genes, but found no significant patterns.

The researchers then looked for crossover between the sex-skewed genes and seven sets of genes previously found to be expressed at atypical levels in postmortem brain tissue from people with autism2,3. The researchers’ list of genes that are highly expressed in males shows significant overlap with two of these sets, one with 361 genes and another with 759 genes that are highly expressed in postmortem autism brains.

Many of the shared genes in these sets are related to microglia, immune cells in the brain that trim away excess neuronal connections, or synapses, in the developing brain and that may be dysfunctional in people with autism. One of the sets also contains genes related to star-shaped cells called astrocytes, which may be involved in learning and memory; these cells are thought to be both smaller and denser in autism brains than in controls.

Finally, the researchers investigated the intersection of the sex-biased genes and 13 sets of genes that characterize certain brain cell types. They identified two gene sets specific to microglia and two to astrocytes that include many of the genes that are elevated in males.

The findings held up in two independent samples: one consisting of 10 adult brains and the other of 8 prenatal brains.

Mosaic minds:

Overall, the findings suggest that male brains are more similar to autism brains in their gene expression patterns than female brains are, says Donna Werling, a postdoctoral fellow at the University of California, San Francisco who worked on the research as a graduate student in Geschwind’s lab.

“But to really test this hypothesis, we would need to do a well-powered study of individuals that include both males and females who are autistic, as well as male and female controls,” Werling says.

It is also unclear how sex-related differences in gene expression arise in the brain. “For example, do males have a greater number of microglia than females do?” Werling says. Alternatively, it is possible that microglia in males express higher levels of these genes than females do, or that other cell types, such as neurons, express microglia genes in men but not in women, she says.

The findings back up the notion that cells other than neurons are involved in autism. “I think this adds support to those ideas that we need to keep our thinking broad in terms of what’s likely to be important or relevant,” Weiss says.


References:
  1. Werling D.M. et al. Nat. Commun. 7, 10717 (2016) PubMed
  2. Voineagu I. et al. Nature 464, 380-384 (2011) PubMed
  3. Gupta S. et al. Nat. Commun. 5, 5748 (2014) PubMed
  • I agree with the point in the article above suggesting that much of the gender bias of autism is real. In other words, it is not just that females are being left out because of poor diagnostic technique. With respect to why autism has this gender bias, I think the answer can be found in testosterone. Even if you control for gender, it appears that elevated testosterone increases autism risk. See: http://www.nature.com/articles/srep06478 for example.

    Why does testosterone increase autism risk? It is in fact typically a metabolic disease of high oxidative stress and often vascular damage. See: http://www.pathophysiologyjournal.com/article/S0928-4680(06)00053-8/fulltext?mobileUi=0 and http://www.ncbi.nlm.nih.gov/pubmed/16908745.

    Testosterone increases oxidative stress and vascular damage. See: http://classic.rspb.royalsocietypublishing.org/content/274/1611/819.full and http://press.endocrine.org/doi/full/10.1210/endo.143.3.8679.

    So it would seem that if somebody has an environmental and/or genetic exposure that increases the risk of autism via upregulation of oxidative stress and vascular damage, then the risk of developing autism will be higher for such an individual if the individual has high testosterone levels. Males have higher testosterone than females. Hence one would expect higher rates of autism among males which is the case.

    By the way this is not just specific to autism. Other diseases of high oxidative stress and vascular damage strike males more than females. For example, just as autism has a gender bias, metabolic syndrome and early death from it has a gender bias as well. See: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.539.110&rep=rep1&type=pdf

    • Ivan Forsch

      It is in fact typically a metabolic disease

      Uh no. It is not.

      “Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation”

      Cited by 2.

      I really find it funny when people who don’t understand how to read or interpret a one-off case study presume to tell everyone what is FACT.

      Your crap has gotten to be beyond annoying, Seth.

      • Hi Ivan,

        Wow. I did not mean to offend you. The point about autism typically being a metabolic disease is that if you look at blood and urine markers in autism they typically show metabolic dysfunction relative to controls. I think that this is unappreciated by many researchers who think of autism as a disease of neurological dysfunction only.

        If you find this offensive or think this is over reaching, for purposes of this discussion one could just say autism often features increased oxidative stress and increased vascular dysfunction.

        I included the link to the ghrelin level study because a finding from it was that boys with autism typically have significantly higher levels of testosterone than controls. In other words this study suggests that higher testosterone is associated with autism.

        • Ivan Forsch

          The ghrelin level study also states “The study was limited to the male sex because of the lack of female patients.”

          For those who are unaware, this type of questionable research has led to troublesome interventions in the past.

          I don’t believe it has any relation or adds anything to Dr. Geschwind’s paper whatsoever.

          • I do not think the ghrelin study represents “questionable research”. I agree the subjects in it were only males. This separate study provides circumstantial evidence that females with autism as a group may have higher levels of testosterone than neurotypical females, but the evidence is only circumstantial. http://www.ncbi.nlm.nih.gov/pubmed/17462645.

            In any case, I agree with you on your broader point that artificial manipulation of testosterone levels in autism through pharmaceutical interventions is a very bad idea, and I am not advocating for it.

            However, I think an interesting question is whether the high levels of testosterone in many males with autism is telling us something else about autism biochemistry.

            Typically in autism the blood sulfate level is low relative to controls. See: http://www.ncbi.nlm.nih.gov/pubmed/21651783. Sulfation is how hormones are metabolized. So perhaps the high levels of testosterone often seen in males with autism is related in some cases to decreased sulfation capacity.

      • Claire Cameron

        Hi Ivan – thanks for reading the article! We’d like to remind you of our commenting guidelines, which are available here: https://spectrumnews.org/about/ As we state in the guidelines, we do not tolerate disrespectful language of any kind. All comments that don’t follow the guidelines will be moderated or deleted. Please work with us to ensure that the discussion forum on Spectrum remains a safe, inclusive space for healthy debate and commentary. If you have any questions, please email [email protected]. Thank you!

        • Ivan Forsch

          Thanks for your prompt attention, @Claire Cameron:disqus I will be more temperate from now on.

          May I also note those same commenting guidelines state “We will delete comments that recommend treatments or contain claims that don’t square with scientific evidence.”

          I believe Mr. Bittker has been warned about this once before.

  • Claire Cameron

    Hi all! Thank you for taking the time to read this story, and for sharing your thoughts. We’d like to remind everyone to read our commenting guidelines before commenting on this article, or any other article on our site. These guidelines are freely accessible here: https://spectrumnews.org/about/ If you have any questions about these guidelines, please email [email protected]. Thank you.

  • Frank Kelly

    Great article and analysis. It was said “It is also unclear how sex-related differences in gene expression arise in the brain”

    I was surprised that no-one mentioned any of the work from Simon Baron-Cohen e.g. Auyeung et al. (2013) Prenatal and postnatal hormone effects on the human brain and cognition. Eur J Physiol. http://www.ncbi.nlm.nih.gov/pubmed/23588379

    A lot of great evidence from the Baron-Cohen folks on the role of testosterone and of the role of foetal testosterone effects on brain and cognition IRRESPECTIVE of the “Autisms” e.g.

    – Eye Contact
    – Vocabulary Size
    – Autistic Traits (social reciprocity, communication)
    – Use of affective language
    – Social relationships and narrow interests
    – Gender-typical play
    – Gender-role behavior
    – Mind-reading
    – Empathy and systemizing

    Indeed they suggest “Sex hormones also have an epigenetic role in changing gene expression throughout development and likely interact with sex chromosome effects on sexual differentiation” with citations.

    Maybe there’s a “there” there, maybe not but the Baron-Cohen folks have been studying the Male-Female differences for almost 20 years and deserve a mention.

    Interestingly a spike in foetal testosterone occurs in a critical window (weeks 8 to 24 of gestation) which blends nicely with the work from Matthew State and Colleagues http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995413/
    where they suggest
    ” we have identified highly significant and robust evidence for the contribution of coexpression networks relevant to L5 and L6 CPNs [cortical projection neurons] in two overlapping periods of midfetal human development (3–5 and 4–6) corresponding to 10–24 PCW. These results strongly support the hypothesis that the marked locus heterogeneity underlying ASD will point to a much smaller set of underlying pathophysiological mechanisms.”

    Its nice to see convergence – even if it turns out to be true for only some of the “Autisms”.

  • Planet Autism

    I am an autistic female, I test as having male brain responses in the brain gender test and my finger ratio is apparently male.

  • Joon

    Could be better with “sex difference”, not “gender difference”. https://en.wikipedia.org/wiki/Sex_and_gender_distinction

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