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Twin study suggests girls are protected from autism risk

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Virginia Hughes
28 February 2013

Double take: Girls don’t have autism-like behaviors unless they come from families at high risk for the disorder, according to the new study.

A comparison of autism-like behaviors in nearly 10,000 pairs of fraternal twins suggests that girls are somehow protected from the disorder1.

The findings, published 19 February in the Proceedings of the National Academy of Sciences, may partly explain why autism is four times more common in boys than girls — one of the oldest and most puzzling statistics in the field.

The study measured autism traits — such as conversational abilities, social preferences and repetitive behaviors — in children in the general population. Among children who have many autism symptoms, girls are more likely than boys to have siblings who also have the traits, the study found.

The findings suggest that girls have a baseline level of protection, and don’t display many autism traits unless they’re “loaded up to the gills with risk factors,” says lead investigator Angelica Ronald, senior lecturer in psychological sciences at Birkbeck, University of London.

Risk factors in these families may include inherited genetic variants, shared environmental influences or some combination of both, she says.

The study does not address the larger question of how this protective effect might work. It might be rooted in biological differences between the sexes. Or it might not really be a matter of protection at all, but rather the result of bias in how clinicians diagnose the disorder, the researchers say.

For example, the male-to-female ratio in autism becomes even bigger for children with high intelligence quotients, suggesting that clinicians and parents may not notice less severe autism symptoms in girls, or may be more primed to look for them in boys.

“I think the approach to this $64,000 question would be having a better understanding of sex differences in autism more generally,” says co-investigator Elise Robinson, instructor in medicine at Harvard Medical School. “It’s very hard to understand differences in the causes of autism between boys and girls if we don’t really understand differences in what gets them diagnosed.”

Family resemblance:

Researchers have long struggled to explain the extreme gender bias in autism. Some have proposed factors, such as high levels of fetal testosterone, that might make boys particularly vulnerable. Others have suggested that girls may be protected through a genetic mechanism related to their second X chromosome2.

Genetic evidence of a possible female protective effect came in 2011, when two studies in Neuron showed that girls with autism are more likely to carry rare, spontaneous copy number variations (CNVs) — DNA deletions and duplications — than are boys with autism. What’s more, the CNVs that girls carry tend to be larger, suggesting that they only get autism when exposed to the most powerful genetic hits3, 4.

“Those original findings could be taken in two ways,” Robinson says. For example, she says, one explanation is a diagnostic bias. “Sure, the girls show more insults, but it’s just because to get diagnosed with autism as a girl, you generally have to be more impaired.”

The other possibility is that there is a bona fide protective effect in girls, she says.

In the new study, she and Ronald investigated whether girls in the general population are protected from autism risk factors that run in families. The study measured autism traits on a continuum, rather than by categorical diagnoses. For example, a child might have some repetitive behaviors without being diagnosed as having autism.

The researchers relied on two large samples of fraternal twins: 3,842 pairs from the Twins Early Development Study in the U.K. and 6,040 pairs from the Child and Adolescent Twin Study in Sweden. Both studies used questionnaires to measure autism traits, such as speech delay or difficulty making conversation, in the twins as children.

The researchers focused on pairs in which one of the twins — dubbed the ‘proband’ — scored in the top five percent of autism trait scores. Siblings of female probands showed significantly more autism symptoms than did siblings of male probands, the study found.

That suggests that girls don’t have autism-like behaviors unless they come from families with high risk, whereas boys can have these traits even in low-risk families.

“This female protective effect idea is something that’s tossed around all the time, but really hasn’t had much strong evidence behind it,” says Lauren Weiss, assistant professor of psychiatry at the University of California, San Francisco. “I think this study provides some very good evidence.”

Researchers would have had to study many more twin pairs to reach the same level of statistical power in a study based on autism diagnoses rather than on traits of the disorder, she adds. 

Serve and protect:

Although the data strongly support the ‘female protective effect’ hypothesis, they don’t completely rule out other explanations, Ronald says.

For example, the questionnaires used to measure autism traits are based on ratings from parents, which are susceptible to cultural biases. What’s more, many instruments used to assess autism and autism-like symptoms were designed and validated largely in groups of boys, who may manifest the symptoms of autism differently than girls do.

The data are also somewhat puzzling in light of older studies on spontaneous risk factors in girls with autism.

The Neuron studies found that girls with autism are more likely than boys to have spontaneous mutations. Because these mutations are not inherited, it would suggest that the girls’ siblings would be less likely to show autism traits — exactly the opposite of the new findings.

“It struck me that on its surface, there seem to be some kind of a contradiction,” says Jeremy Silverman, professor of psychiatry at Mount Sinai School of Medicine in New York, who was not involved in the new work.

However, Robinson says that because spontaneous mutations are rare in the general population, they wouldn’t be expected to play a “meaningful role” in this sample.

Robinson and Ronald are next looking at whether specific genetic risk factors for autism and related disorders are more likely to lead to traits of the disorder in boys than in girls. If the female protective effect hypothesis is correct, then “you should see a greater trait burden in boys who carry these risk factors than girls, on average,” Robinson says.

Everybody agrees that the autism field would benefit from more studies of girls with the disorder, who have historically been ignored

“Understanding the sex difference is going to help everyone, boys and girls with autism,” Ronald says. “It’s part of the whole mechanism by which autism develops.”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1. Robinson E.B. et al. Proc. Natl. Acad. Sci. U S A Epub ahead of print (2013) Abstract

2. Skuse D.H. Pediatr. Res. 47, 9-16 (2000) PubMed

3. Levy D. et al. Neuron 70, 886-897 (2011) PubMed

4. Gilman S.R. et al. Neuron 70, 898-907 (2011) PubMed

Comments

Name: passionlessDrone
28 February 2013 - 4:14PM

Hi Virginia Hughes -

Did any of the people you spoke to while writing this comment on an potential mechanisms of action by which females *seem to be* protected?

Specific toward autism, we might look to:

Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism

which observed feedback loops in proteins known to be implicated with autism risk and estrogen/testosterone, including: "The existence of shared gene targets may explain why females, with higher levels of estrogens, are less susceptible to autism. That is, estrogens may not only protect females against autism by increasing the level of RORA expression, but also by inducing shared target genes of RORA through ER, thus compensating in part for RORA deficiency."

Similarly, but from a more generalized standpoint, we keep on seeing data regarding altered microglial / neuroimmune function in autism (and nearly every other behavioral disorder), and estrogen has been shown to be protective of the development of a state of neuroinflammation; i.e.,

Estrogen modulates TNF-alpha-induced inflammatory responses in rat aortic smooth muscle cells through estrogen receptor-beta activation

Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

Or a great many others.

Very nice write up.

- pD

PS: Do you have the ear of SFARI web admins? You've got very, very good autism content (yah!), and among the worst commenting / notification systems (boo!).

Name: Emily Singer
28 February 2013 - 4:31PM

Thanks for the comment and the feedback. We're working hard to make the login and comment system easier to use and should have a fix in place soon.

Name: Greg Boustead
5 March 2013 - 10:46PM

Yes, as Emily mentions, we have steps in place to improve the login system on SFAR.org, and we're always looking for ways to make commenting as useful and user-friendly to readers as possible.

Feedback from users is invaluable. If you have any specific issues, suggestions, or desired features re commenting, please send them to community@sfari.org, and I'll see how we can address them. Thanks again for your feedback!

Name: Virginia Hughes
28 February 2013 - 4:39PM

Thanks for reading, pD.

I think the researchers were (rightly) hesitant to comment on potential mechanisms, as their data really doesn't point to one or the other.

Although they said that the risk factors could be environmental or genetic, it's hard for me to imagine an environmental risk factor that would affect one sex more than the other. All of the big environmental influences on autism -- paternal age, in utero infections, pregnancy complications, say -- would affect girls just as much as boys. So my bet would be that the protection is some kind of gene-gene interaction or, as you suggest, hormonal.

Name: ASD Dad
2 March 2013 - 1:42AM

Sex Differences in the Response to Viral Infections: TLR8 and TLR9 Ligand Stimulation Induce Higher IL10 Production in Males

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039853

Viral infection has a long history of association with autism including mumps , rubella and influenza.

Name: Anonymous
2 March 2013 - 1:55AM

Sex differences in the response to viral infections: TLR8 and TLR9 ligand stimulation induce higher IL10 production in males.

http://www.ncbi.nlm.nih.gov/pubmed/22768144

Neonatal levels of cytokines and risk of autism spectrum disorders: an exploratory register-based historic birth cohort study utilizing the Danish Newborn Screening Biobank.

http://www.ncbi.nlm.nih.gov/pubmed/22917523

"Findings showed that children developing ASD were more likely to have decreased levels of both T helper-1(Th-1)-like cytokines (i.e. IFN-γ) and Th-2like cytokines (i.e. IL-4, IL-10) which may suggest a depressed or hypoactive immune cell activity during neonatal period in ASD."

Amniotic fluid inflammatory cytokines: Potential markers of immunologic dysfunction in autism spectrum disorders.

http://www.ncbi.nlm.nih.gov/pubmed/22175527

"Results. Overall, individuals with ASD had significantly elevated AF levels of TNF-α and TNF-β compared to controls. Analyzing individuals diagnosed only with ICD-10 codes yielded significantly elevated levels of IL-4, IL-10, TNF-α and TNF-β in ASD patients. Restricting analysis to infantile autism cases showed significantly elevated levels of IL-4, TNF-α and TNF-β compared to controls with no psychiatric comorbidities. Elevated levels of IL-6 and IL-5 were found in individuals with other childhood psychiatric disorders (OCPD) when compared to controls with no psychiatric comorbidities. Conclusions. AF samples of individuals with ASD or OCPD showed differential cytokine profiles compared to frequency-matched controls. Further studies to examine the specificity of the reported cytokine profiles in ASD and OCPD are required."

Name: Anonymous
2 March 2013 - 1:45PM

Of course there was this recent article in Science

http://www.sciencemag.org/content/339/6123/1044.short

Welcome to the Microgenderome

"The gender bias observed in numerous diseases has long been understood as an entirely host-intrinsic factor. It is one of the many puzzling features of some autoimmune conditions (inappropriate immune responses that attack self antigens and destroy host tissue) including type 1 diabetes mellitus, in which sex hormones affect disease susceptibility and severity (1, 2). On page 1084 of this issue, Markle et al. (3) introduce an astonishing twist to this view, suggesting that gender bias may be exercised and/or reinforced by the commensal microbiota of the host. This extrinsic, albeit commensal, factor appears to regulate sex hormone levels and arguably the gender bias observed in type 1 diabetes mellitus. The finding contributes to an expanding field of translational research aiming to convert our growing knowledge of the host-microbiota relationship into therapeutic approaches. "

The gut, viruses, gender and autism ...

Name: Mark
5 March 2013 - 6:09PM

A sensitive reading of Darwin Origin of Species, will yield valuable understanding of the genderization of reproduction- the Invention of Sex has a pre mamalian history of the order X100 say. A scientific study which ignores this baggage will always churn more questions than answers. The definition in scientific terms of such a complex system must produce a blurred image unless it is able at least to differentiate the discrete and therefore unrelated subsets which any complex pathway must yield. The general point of 'most puzzling' statistical bias to male 4-1 seems to me a serious concern that basic evolution -genetics and sexual development biology are absent from the research skillset. Should we be concerned that such a gap persists.An opportunity exists for a groundbreaking competitive and collaborative research fasttracker to identify useable research. The information is all there but is being buried by the random complexity.We could be one move away from a breakthrough or like ships in the night never even knowing how close we are.

Name: RA Jensen
6 March 2013 - 11:45AM

Virginia you wrote: 'it's hard for me to imagine an environmental risk factor that would affect one sex more than the other'.

Environmental risk factors can affect one sex more than the other and has been seen in Klinefelter syndrome. Klinefelter syndrome is the fasted growing genetic syndrome that is diagnosed only in newborn males and occurs in 1 to 500 -1,000 newborn males. Klinefelter syndrome is not inherited and is always caused by an extra X chromosome. Half the cases (53%) are caused by an XY sperm mutation and half (47%) are caused by an XX egg mutation producing the XXY Klinefelter syndrome genotype. Klinefelter syndrome is associated with increased autism risk.

http://ghr.nlm.nih.gov/condition/klinefelter-syndrome

McAuliffe’s group recently (2011) examined the sperm in males recruited from a fertility clinic and found that all the volunteer males had produced XY sperm. They then examined the level of exposure to PCB congeners as measured in blood. Increased level of exposure to PCB congeners was associated with increased production of XY sperm. There is also a paternal age effect seen in Klinefelter syndrome. PCB congeners have a long-lasting half-life and can build up over time in humans with continuous exposure increasing the risk of producing XY sperm. Lowe examined the sperm in fathers of Klinefelter syndrome boys and found that increased production of XY sperm was associated with increasing paternal age. None of the fathers possessed the XXY mutation, the mutations were found only in reproductive cells (sperm).

References

Lowe X, Eskanazi B, Nelson D, Kidd S, Alme A. (2001). Frequency of XY Sperm Increases with Age in Fathers of Boys with Klinefelter Syndrome. Am J Hum Genet. 2001 November; 69(5): 1046–1054.

McAuliffe ME, Williams PL, Korrick SA, Altshul LM, Perry MJ. (2012). Environmental Exposure to Polychlorinated Biphenyls and p,p´-DDE and Sperm Sex-Chromosome Disomy. Environ Health Perspect. 2012 April; 120(4): 535–540.

Ross JL, Roeltgen DP, Kushner H, Zinn AR, Reiss A et al. (2012). Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics Apr;129(4):769-78.

Name: RA Jensen
6 March 2013 - 12:31PM

One of the most replicated findings in recent autism research is that advanced parental age (maternal and paternal) is associated with increased autism risk. The twin study reviewed is not a study of strictly diagnosed autism, it is a study taken from general population twins that measure what has been called autistic-like traits. Without a doubt what has been called under various labels such as autistic-like traits, the broader autism phenotype and sub threshold autistic-like traits is one of the most consistent findings in autism research. Autism is a multifactorial disorder and the broad autism phenotype influence may always be reliant on other genetic factors, inherited or de novo, environmental risk factors and epigenetics that are involved in the transition to strictly defined autism.

One of the scientists you interviewed, E. Robinson, published a paper that measured the effect of parental age in a large sample of general population children and found ‘There was no association between parental age and social-communicative autistic traits in the general population. Neither maternal nor paternal age was associated with extreme scores. These findings suggest that advanced parental age does not confer increased risk for extreme social and communication impairment assessed quantitatively’.

This new finding, which needs to be replicated, is consistent with the concept that autism is multifactorial and ‘autistic-like traits’ are a contributing, but not a causative factor and is consistent with autism being both a categorical condition and a dimensional condition.

http://www.ncbi.nlm.nih.gov/pubmed/21350918

Name: breanna
27 February 2014 - 9:40PM

i needs some answers

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