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News

Power of girls to thwart autism shows up in sibling study

by  /  28 May 2015

Simxa/Shutterstock.com Family ties: Younger siblings of girls with autism are at increased risk of the disorder.

Children whose older sisters are on the spectrum are at higher risk for autism than are those with affected older brothers, suggests a new study. The study also found that younger brothers of children with autism are at greater risk than younger sisters1.

The findings, published 13 May in a special issue of Molecular Autism on gender differences, support the notion that girls are somehow protected from autism. They also suggest that this protection helps explain the lopsided ratio of boys to girls with the disorder.

Identifying factors that protect girls from autism could lead to new therapies, says senior researcher Daniel Geschwind, director of the University of California, Los Angeles Center for Autism Research and Treatment. “If they protect females, then maybe they can be used to protect males as well.”

Geschwind’s team looked at data from 1,120 families in the Autism Genetic Resource Exchange, a bank of information and biological samples from affected families. All of the families have two or more children with autism and 341 of the families also include at least one sibling younger than a child on the spectrum.

The researchers found that children who have an older sister with autism have a 44 percent chance of receiving an autism diagnosis, compared with 30 percent for those with an affected older brother. These results suggest that girls need a stronger genetic hit to develop autism.

Adding further support for this theory, boys with an older affected sibling are more than twice as likely as girls with an older affected sibling to be diagnosed with autism.

“This is a fantastic analysis supporting the existence of the female protective effect,” says John Constantino, professor of psychiatry and pediatrics at Washington University School of Medicine in St. Louis, who was not involved with the study. “If it’s true that the female protective effect exists, it’s the most potent protective influence we know of when it comes to autism.”

Gender shield:

Many previous studies have not found patterns in autism occurrence in a family that back the female protection theory. In many cases, however, these studies relied on families with only one child on the spectrum. Autism in these families tends to stem from severe, spontaneous mutations that are just as harmful in girls as they are in boys, says Constantino. “When you look at forms of autism that are combined with, say, mental retardation, the sex ratio is actually 1-to-1,” he says.

By studying families with more than one child on the spectrum, Geschwind and Donna Werling, then a graduate student in his lab who did the bulk of the work, homed in on heritable risk factors shared among siblings.

Apart from studying siblings of different ages, Werling and Geschwind also looked at 193 fraternal twin pairs. They found that boys whose twin brothers have autism had a 59.1 percent risk of the disorder. This risk rose to 71.4 percent for boys whose twin sisters are on the spectrum.

The researchers also found that the chances of autism recurring in families is greater when births are close together. This result adds to mounting evidence that certain environmental factors, such as nutrient deficiencies in the womb, might raise the chances of autism. Intriguingly, when the researchers explored this birth interval effect by gender, it held up only for males. So girls may be shielded from environmental risks, too. 

The findings stop short of providing a possible mechanism for a protective effect in girls and women. Another paper published in the same issue found no evidence for a genetic hotspot underlying the phenomenon2. It’s more likely, that study concluded, that multiple genes collaborate to guard girls from autism.

The unveiling of these protective influences awaits larger studies with more girls in them, says Lauren Weiss, assistant professor of psychiatry at the University of California, San Francisco3. “Having larger datasets available would enable additional observations or analyses.”

1. Werling D.M. and D.H. Geschwind Mol. Autism 6, 27 (2015) PubMed

2. Gockley J. et al. Mol. Autism 6, 25 (2015) PubMed

3. Button K.S. et al. Nat. Rev. Neurosci. 14, 365-376 (2013) PubMed


  • Seth Bittker

    These researchers are making the search for the cause of the female gender protective affect in autism too complicated.

    Autism often features high levels of oxidative stress and vascular damage. Higher levels of testosterone upregulate oxidative stress and vascular damage. In addition those with autism often have higher than normal levels of testosterone to begin with.

    So I would suggest that the primary protective effect of being of female gender in autism risk is the lower testosterone load.

    • Amanda

      Totally agree…These studies are so redundant. It is all about testosterone. Can we move on?

    • Teena

      Imagine my son daughter and youngest daughter all were diagnosed withASD so not sure this research is valid !!

    • Mark

      It seems that the fundamental of genetic processes marked by Mendel 1865-6, and controversially later ‘re-discovered’ by a gaggle of scientific claimants remains in obscurity even today. That original research was launched into an environment where it could not thrive in the open , but has been essentially archived as a ‘recessive trait’, as generally recessive traits are lodged with the female (here they remain unexpressed, but able to be passed by mother to sons (50% expressed) and daughters(0% expressed). The question of why gender should arise in the evolutionary process is also of interest, as it is the birthplace of a son ( or modified female that he represents).
      Gender provides a process for testing genes in the environment through the male, prior to their expressed emergence in the gene pool. Seasonal environment changes provide triggers in the expression of some genes, essential for procreation or camouflage survival. So there are plenty of areas for new research to aim at. If I am barking up the wrong tree, and this research has something new to offer please respond. Autism is a complex area, but the reality is perhaps not acceptable in our present culture, so will persist only as an archived recessive.

    • Matt Carey

      This is the sort of “off the cuff” statement that demonstrates how little the autism parent community understands basic biology.

      While testosterone levels are higher in male infants, by 7 months, the levels are comparable in males and females
      http://www.childrensmn.org/manuals/lab/Chemistry/028136.pdf

      and this continues until puberty.

      One might also consider this study of sex hormone levels in cord blood
      http://www.ncbi.nlm.nih.gov/pubmed/26085846

      What study are you basing the “vascular damage is higher in autistics” idea? Because I just did a search of pubmed with “vascular damage” and autism with on hit, and that wasn’t relevant.

      And if autistic children have higher levels of oxidative stress, but the testosterone levels are comparable in males and females below age 10, how does that fit your hypothesis?

  • brian

    Given the preponderance of males among those affected by ASD, sex-linked genes remain of interest in the disorder. Functional variants of X-linked genes were found in five of 30 females with autism from multiplex families in this recent exome-sequencing study, which examined only a tiny fraction of the genome and so by design ignored possible mutations that might affect many regulatory processes: Int J Mol Sci. 2015 Jan; 16(1): 1312–1335. It’s also worth noting that postmortem brain samples from individuals with ASD commonly show abnormal levels of the product of the X-linked MECP2 gene; frank mutations in this gene cause Rett syndrome in females and are usually fatal in males, but changes in gene expression affecting the single gene copy in males might be more easily revealed and less than in females.

  • Planet Autism

    Of course they are missing the fact that with the gender disparity with girls being included in research, because they often aren’t identified in the first place, this study won’t be accurate when it comes to girls being “protected” from having autism…

    I absolutely disagree that there is any gender ratio difference in autism, I believe it’s 1:1 and I recently heard Tony Attwood declare his belief to be the same.

    When you have diagnostic criteria that were based entirely on males, how the heck can you expect to get accurate research if females are not being referred or diagnosed in the first place!

  • Planet Autism

    As for testosterone, autistic females are affected by this too. Females with autism have more male brains than control subjects, having brains more like non-autistic males. If you start off with less testosterone, even if you get the same exposure to higher levels of testosterone, you will still end up with a lower overall effect.

  • Alex

    Couldn’t the increased risk with shorter inter-birth interval be due to environmental deprivation (less time for parents to interact in meaningful communication) before the birth of the next child? And the sex difference could be influenced by parents making more eye contact and talking more to daughters than sons during very early development?

  • Leigh

    When boys have autism in a family it is often more obvious, so other children may be overlooked if they are not as affected in social or communication issues at school. I think this is looking in the wrong direction: girls are not protected, but high-functioning girls with autism look different to boys, that is the real problem.

  • Leigh

    Also, high-functioning autism runs across my family, male and female, back 3 generations…just because it wasn’t diagnosed, doesn’t mean it didn’t exist. This is not nutrition, this is not environment, this is genetic make-up.

  • Kay

    Don’t believe it at all, I still think girls are falling under the radar. Just as many girls/women in my family are affected, we just present in a subtle way that is often missed.

  • Michelle

    “thwart” is misleading. I’d suggest “conquer the challenges posed by non-autistics” would be more appropriate.

    • Anonymous

      agree.

  • Anonymous

    as an autistic, i’m skeptical of the female ‘protective’ effect and also bothered by it. studies of it seem to be based on definitions of autism based on observations of males not females. so what can you really conclude until this ‘effect’ is shown in a sample where definition of autism takes account of differences between autistic men and women? also what are the implications of this effect for autistics? so do the researchers studying this recommend that having a girl with autism beware having more children? seems unhelpful to me.

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