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.

35 Responses to “Why are autistic people mainly male?”

  1. Suvi-Tuuli Allan September 17, 2010 at 11:49 #

    Not all male humans have XY chromosomes, not all female humans have XX chromosomes. Know this!

    • Kev September 17, 2010 at 12:08 #

      Agreed, but lets say ‘in the main’ 🙂

  2. Proofreader September 17, 2010 at 12:28 #

    Autisitc – typo

    “geier’s” and “embryo’s” don’t own anything in these sentences. They are merely plural and should not have apostrophes.

    • Kev September 17, 2010 at 14:52 #

      LOL…you people are busting my balls here 😉

  3. daedalus2u September 17, 2010 at 14:22 #

    This idea to explain the gender bias of ASDs is not correct.

    If there was a deletion on the X chromosome sufficient to cause the male excess, that would have absolutely jumped out of the whole genome scans that have been done.

    A second X chromosome does not “protect” females from the loss of a gene on one X chromosome. Females are mosaic, of their two X chromosomes, one is inactivated in somatic tissues. This is the issue with Rett Syndrome. RS is caused by a loss of the MeCP2 gene (on the X chromosome) and the MeCP2 protein which binds to methylated DNA and regulates its output.

    Males with MeCP2 deletion die in utero. The presence of some cells with MeCP2 somehow “rescues” females from death, but not from RS. That “rescue” is not due to expression of MeCP2 in cells where the MeCP2 containing X chromosome has been silenced.

    My explanation of the gender bias in ASDs is that it results from estrogen increasing NO levels and testosterone decreasing NO levels. This explanation is also consistent with the sub-clinical ASD-type characteristics that are more common in males than in females.

    SBC’s “extreme male brain” is not the correct way of looking at it. ASDs have an “extreme low NO brain” and males tend to have a lower NO brain, so there are some similarities. It is the NO that comes first and is the main driver, the steroid hormones modulate the NO levels and there is feedback and hysteresis so it is very complicated (and not modifiable externally via things like lupron).

  4. Emily September 17, 2010 at 15:43 #

    Frankly, when there’s a male bias like this, the most reasonable first place to look is the X chromosome. Prediction: There will be more.

  5. Jake Crosby September 17, 2010 at 16:28 #

    “Thus, our systematic screen of PTCHD1 and its 5′ flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.”

    That really explains everything…

    Prediction: The next genetic study does not replicate this at all, but finds a new 1% “association” in yet another gene never-before-mentioned in relation to autism. And the cycle continues to repeat.

    • Kev September 17, 2010 at 16:43 #

      Jake, maybe you didn’t read the blog entry properly 🙂 thats OK it’ll still be here next time you visit.

  6. vmgillen September 17, 2010 at 16:49 #

    Yeah – let’s also look at idiosyncratic amygdalas – like, usually seen in males – has nothing to do w/ASD Dx except shared symptoms (and that’s ASD: a list of symptoms, not a Dx – another train of thought…)

    I still have an automatic knee-jerk reaction to the “X” theories – and even to the Fragile “X” Dx – it’s crazy, I know, but it sure does feel like blame the mother/woman- at least until my active thought-processor kicks in.

  7. daedalus2u September 17, 2010 at 16:51 #

    I submitted a comment which is still held up. I don’t think this will be important. If X chromosome stuff was responsible for the gender bias, that would have shown up in the whole genome surveys. The male bias is gigantic. That doesn’t mean what is causing the male-female differences is on the X chromosome. Males are larger than females (on average). That isn’t because genes for being small are on the X chromosome.

  8. Chris September 17, 2010 at 17:44 #


    I still have an automatic knee-jerk reaction to the “X” theories

    Does that hold true for color blindness?

  9. Dawn September 17, 2010 at 20:33 #

    @Chris: depends on the type of color blindness. I remember being amazed during nursing school about the numerous types, and finding that I and several other of my classmates, have versions of colorblindness. No one had complete color blindness though (monochromancy) which, indeed almost always occurs in males.

    Although I know it doesn’t hold for all levels of ASD, I wonder how many mildly affected females are never diagnosed because they fit in with their family or societal mores on “how girls should behave”.

    To be honest, if I had had a child who, for example, rocked, cried and screamed, had clothing/textile/food issues, with no obvious AD issues (regression, lack of eye contact to name only a few), that child would not have been diagnosed because of the numerous family members in the past and present who display (or used to display as a child but don’t any longer)some/all of those behaviors.

  10. Chris September 17, 2010 at 20:49 #

    Dawn, it does seem hard to pin down autism as just one thing. So that would seem to make it difficult to pin down one specific cause.

    By the way, have you seen this article on the first person who was diagnosed by Kanner: Donald T?

    It is being discussed here.

  11. Roger Kulp September 17, 2010 at 21:13 #

    What,nothing about mercury-testosterone “sheets”?

    I would like to see them extrapolate this,to apply to families where siblings of both sexes are autistic,with the male sib more severely affected.

  12. Emily September 17, 2010 at 21:58 #

    The assumption of a huge male bias would be out the window if it’s revealed that rates of autism among females are higher than currently recognized.

    Regardless, given the complexity of dosage compensation, it still makes sense to me that changes in X chromosome loci–whether duplications, deletions, inversions, etc.–will be relevant in some cases. (and an inversion can still result in differences vs. a deletion; example is William’s Syndrome, in which children wtih an inversion have less intense manifestations than children with a deletion).

    I mean, your obvious options here are to go to the X (as in the chromosome) or go to the T, as in testosterone (and DHT) when you see this kind of extreme sex bias…if the sex bias *is* there or is as extreme as assumed. I’d back it because while we teach that women “shut down” one of their X chromosomes in each cell, the fact is that the shut down is not complete and the percentage of genes that remains active varies from woman to woman, not to mention the mosaicism that results from the presumably random shutdown of an X in each cell. If autism is X related, these vagaries of dosage compensation and mosiacism would explain why it might manifest more clearly in some women (greater mosiacism favoring one X over another) than in others.

    In other words, I predict more of such findings. XX and XY and related inheritance are far more complex than basic biology information would suggest.

  13. Emily September 17, 2010 at 22:33 #

    Roger, see what I wrote above. X chromosome “silencing” is a funny thing.

  14. daedalus2u September 18, 2010 at 00:18 #

    But Emily, wouldn’t the effects you are postulating be obvious in whole-genome surveys in thousands of individuals and their near family members? Like in this one?


    They looked at 1558 families and 4712 individuals.

    The cases were 84% male and 16% female, a 5 to 1 ratio.

  15. passionlessDrone September 18, 2010 at 01:00 #

    Hi Emily –

    I mean, your obvious options here are to go to the X (as in the chromosome) or go to the T, as in testosterone (and DHT) when you see this kind of extreme sex bias

    What about going to the ‘E’ as in estrogen? It does seem to be protective for things like neuroinflammation. Anyways, just a thought that it could be contributing.

    – pD

  16. Emily September 18, 2010 at 01:49 #

    “All of these results spring from a relatively small sample size for GWA studies (n ? 1369 families), limiting both our power to detect association and the certainty of the associations detected.” And they looked at SNPs. And there’s certainly very little known about potential epigenetic interactions, etc., including the possibility of methylation differences. Given the strong role of methylation in X chromosome regulation, that wouldn’t surprise me, either. From the range of phenotypes, a complex level of interactions involving a wide spectrum of alleles but tracing to some epigenetic switch of some kind might not be out of the question.

  17. daedalus2u September 18, 2010 at 03:16 #

    Yes, I read their post hoc statement that their sample size was too small too.

    You can’t find epigenetic stuff because most of that happens in utero during differentiation and you would have to destroy the tissues that have been differentially epigenetically programmed (i.e. the brain) to measure what epigenetic programming there is.

    If it is epigenetic stuff, then “the problem” won’t be found in “the genes”, but rather in the differential regulation of epigenetic programming in utero. A large amount of that epigenetic programming in multiple tissue compartments is known to be differentially regulated by differences in nitric oxide.

  18. daedalus2u September 18, 2010 at 03:19 #

    I just remembered after I posted that we know that differential readout of epigenetically programmed DNA is sufficient to produce the “autism-like” symptoms of Rett Syndrome. In the RS mouse model, turning off MeCP2 recapitulates the RS symptoms exquisitely well. Turning MeCP2 back on makes those symptoms go away.

  19. Clay September 18, 2010 at 05:53 #

    As for what some curbie anti-autism ‘advocates’ believe, Jake Crosby thinks his autism was caused by his mother’s dental fillings, Oliver Canby thinks he was poisoned by thimerosal, while Jonathan Mitchell credits his autism to his “precarious pecunius”. Yet, they’re all looking for the same cure, and say that we’re actively preventing them from getting it. None of them make any sense.

  20. Emily September 19, 2010 at 00:25 #

    Daedalus…”they” are also finding that epigenetic changes can be heritable (see, e.g., diethylstilbestrol). Very complex stuff.

  21. Emily September 19, 2010 at 17:38 #

    pD…sorry, for some reason, I didn’t see your post. E is actually the active formative hormone in the mammalian male brain. T is aromatized there to E2 (or at least, the last I read, that was the going mechanism), and E2 “masculinizes” the brain. And when it comes to male-biased patterns, E doesn’t play much of a role in etiology and looking at E would be several steps beyond the other more parsimonious explanations. As many autoimmune disorders are female-biased, I think E might be more deleterious than not, although there are reports that E during pregnancy mitigates MS symptoms, so there is that anti-inflammatory possibility there. However, not likely to be involved in the strong male bias here.

  22. daedalus2u September 20, 2010 at 01:45 #

    From the abstract of this paper:


    “Estrogen decreases cerebral vascular tone and increases cerebral blood flow by enhancing endothelial-derived nitric oxide and prostacyclin pathways. Testosterone has opposite effects, increasing cerebral artery tone. Cerebrovascular inflammation is suppressed by estrogen but increased by testosterone and progesterone.”

    E2 causes the release of NO when it activates the ER. I think this is why autoimmune stuff and migraines tend to decrease at the time of ovulation and during pregnancy.

  23. dr treg September 20, 2010 at 08:22 #

    Dendritic spine morphology and the immune system are abnormal in autism.
    Sex hormones affects dendritic spine growth and this may contribute to the sex ratio as well.
    1. Testosterone reduces dendritic growth.
    2.Estrogen promotes dendritic growth
    3. Sex hormones affect dendritic spine growth in adulthood.
    The reduced estrogen at certain times in the female life e.g. pre-menstrually, post-natally and menopausally result in reduced dendritic arbors in the frontal lobes and subsequent fear, self-pity and resentment often with some element of OCD.

  24. smarter than you September 20, 2010 at 17:06 #

    Kev…you are so fucking lost..your own people are even calling your stupidity out!

    • Kev September 20, 2010 at 17:37 #

      Really? Or maybe its just OK to have open debate here 🙂

  25. RAj September 20, 2010 at 18:43 #

    Genetic variations have been detected in regions in every chromosome. They are called candidate ‘autism’ genes, but no gene specific to autism has ever ben identified. These genetic anomolies are primarily mental retardation susceptabilty genes. The same exact gene variants that have been invoked as candidate’autism’ genes, have also been invoked as candidate genes for schizophrenia, mental retardation, speech and language impairments, ADHD and others.

    There is so far, no genetic variant that can be thought of as representing a diganosis specific candidate gene. At a higher conceptual level they can be thought of as representing candidate genes for increased risk for atypical brain development.

  26. RAj September 20, 2010 at 21:48 #

    Furthermore, the PTCHD1 gene proposed as an ‘autism’ gene was first identifed earlier this year as a candidate gene for X-linked intellectual disability.


  27. Corina Becker September 26, 2010 at 08:23 #

    erg, talking genetics so specifically is a bit out of my league.

    I’m confirming some facts though; currently, hasn’t researched suggested that there are more than one gene that is responsible for autism? With a possible environmental cause (by which I mean, like in the womb [sorry, late at night, can’t think of proper term])?

    Currently, what are the limits of genetic engineering? I heard somewhere that we don’t have to worry about Autism being genetically engineered out since science at this time can only genetically engineer single genes, and the results aren’t always guaranteed. and since Autism is multi-gene, we don’t have to worry. Or something like that.

    And third, What about all the autism specialists and growing awareness that the rate of boy to girls on the autism spectrum isn’t what we think; that it’s closer to being 2:1 or even 1:1, but because Autism manifests differently in females, girls are often under-diagnosed?

    Given the testimonies of parents, and mothers who, while getting a diagnosis for their child, has had a professional suggest that they too, are autistic, I would be interested in seeing some research done on how much of perceived autism characteristics are more male specific, and what are the autism characteristics for females, and then coming to a better incident rate.

  28. esattezza November 26, 2010 at 18:33 #

    D2u wrote:
    “I don’t think this will be important. If X chromosome stuff was responsible for the gender bias, that would have shown up in the whole genome surveys. The male bias is gigantic. That doesn’t mean what is causing the male-female differences is on the X chromosome. Males are larger than females (on average). That isn’t because genes for being small are on the X chromosome.”

    While I agree with you that mutations on the X are unlikely to account for the gender bias in its entirety (particularly as recent studies have shown a Dx bias), I do have to point out that the second part of your statement, while technically correct, is not the whole story. Genes that regulate growth are often found in imprinted regions, which are regulated by DNA methylation. Therefore, genes the impact methylation, including MecP2 (on the X) could have an impact there. I have no direct knowledge of this, but I would suspect that other genes responsible for sex differences may also be found in imprinted regions that are somehow regulated my X chromosome gene product.

    Furthermore, there are some genes that escape X inactivation, creating different dosages between males and females. This alone could make males more sensitive to changes elsewhere in the genome or to environmental triggers.

    Lastly, adding to/clarifying the MeCP2 discussion. MOST mutations in MeCP2 lead to Rett in girls and are embryonic lethal in males. However, skewing of X inactivation or secondary mutation can lead to girls with only mild developmental delays. Similarly, these same secondary mutations can lead to boys with Rett, or even with autism depending on the severity of the mutation.

    Sorry, I know this thread’s been dormant for a while (I just started actively reading LBRB), but I thought I could provide some useful info.

  29. David N. Andrews M. Ed., C. P. S. E. August 25, 2011 at 02:23 #

    STY …

    Dx: verbal diarrhoea.
    Rx: cork, insertion into anal orifice.
    Px: not good. still comes out with shit, no matter what is done.

  30. chris mackay May 12, 2012 at 00:38 #

    Some actual “proven” answers would be nice……..I have a 5yr old with autism and although his school are great with him, the so called experts won’t say a thing about his development for fear of being wrong……we need money for more research and shouldn’t have to rely on a few doctors trying to make a name for themselves in what they consider to be an obscure field!!



  1. Is music taste gendered?: BBC6, RYM, High Fidelity | decemberembers - August 24, 2011

    […] in men, but the reasons for this are unclear: while most research is into genetic differences (a 2009 study inconclusively suggests that the answer lies in the XX/XY chromosomes) , there is a strong […]

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