Unsolved Mystery

Why Are Autism Spectrum Conditions More Prevalent in

Males?
Simon Baron-Cohen1*, Michael V. Lombardo1, Bonnie Auyeung1, Emma Ashwin1, Bhismadev
Chakrabarti1,2, Rebecca Knickmeyer1,3
1 Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom, 2 Centre for Integrative Neuroscience and Neurodynamics,
School of Psychology and Clinical Language Sciences, University of Reading, Reading, United Kingdom, 3 Department of Psychiatry, University of North Carolina–Chapel
Hill, Chapel Hill, North Carolina, United States of America

in Attention Deficit and Hyperactivity Disorder (ADHD), dyslexia,

Abstract: Autism Spectrum Conditions (ASC) are much conduct disorder (CD), specific language impairment, Tourette
more common in males, a bias that may offer clues to the Syndrome, and Learning Difficulties (see Table 1) [10].
etiology of this condition. Although the cause of this bias However, the male bias is much more pronounced in ASC,
remains a mystery, we argue that it occurs because ASC is especially in the case of AS. This male bias could simply reflect the
an extreme manifestation of the male brain. The extreme difficulty of diagnosing AS in females. Though classic autism
male brain (EMB) theory, first proposed in 1997, is an
would not be missed in females, AS could be if it presented as some
extension of the Empathizing-Systemizing (E-S) theory of
typical sex differences that proposes that females on other condition, such as anorexia [11] or borderline personality
average have a stronger drive to empathize while males disorder [12], both of which involve the exercise of excessive
on average have a stronger drive to systemize. In this first control over the environment or other people, and a certain degree
major update since 2005, we describe some of the of a self-centeredness. Equally, AS in females could be under-
evidence relating to the EMB theory of ASC and consider diagnosed if females are more motivated to learn to conform
how typical sex differences in brain structure may be socially or have better imitation skills that allow them to ‘‘pretend
relevant to ASC. One possible biological mechanism to to be normal’’ [13]. Finally, this male bias might reflect the
account for the male bias is the effect of fetal testosterone inability of the widely used diagnostic instruments (the Autism
(fT). We also consider alternative biological theories, the X Diagnostic Observation Schedule (ADOS) or Autism Diagnostic
and Y chromosome theories, and the reduced autosomal Interview-Revised (ADI-R)) to detect the more subtle ways in
penetrance theory. None of these theories has yet been which AS may present in females.
fully confirmed or refuted, though the weight of evidence While these explanations of mis- or under-diagnosis may
in favor of the fT theory is growing from converging explain part of the male bias, there may also be biological reasons
sources (longitudinal amniocentesis studies from preg- for the male bias in ASC. We argue that the bias can be
nancy to age 10 years old, current hormone studies, and
understood as an extreme expression of the psychological and
genetic association studies of SNPs in the sex steroid
physiological attributes of the male brain; that is, males need only
pathways). Ultimately, as these theories are not mutually
exclusive and ASC is multi-factorial, they may help explain slight psychological and physiological changes to exhibit ASC
the male prevalence of ASC. while females would require more, thus making ASC rarer in
females. What factors might favor overdevelopment of male
characteristics? One possible biological mechanism could be the
masculinizing effect of fetal testosterone (fT). Two other
Is There Really a Male Bias? possibilities include the X- and Y-linked theories and the reduced
The diagnosis of classic autism and Asperger Syndrome (AS),
known as Autism Spectrum Conditions (ASC), rests on difficulties Citation: Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B,
et al. (2011) Why Are Autism Spectrum Conditions More Prevalent in Males? PLoS
in reciprocal social interaction and communication, alongside Biol 9(6): e1001081. doi:10.1371/journal.pbio.1001081
strongly repetitive behavior and unusually narrow interests [1].
Published June 14, 2011
The prevalence of ASC is estimated to be 1% [2,3]. A diagnosis of
classic autism, unlike AS, also requires the presence of additional Copyright: ß 2011 Baron-Cohen et al. This is an open-access article distributed
learning difficulties and language delay. ASC is neurobiological, under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
evidenced by atypical brain development in structure and function original author and source are credited.
[4]. ASC is also genetic [5,6] though not without some interaction
with environmental influences. Funding: MRC, Wellcome Trust, Nancy Lurie Marks Foundation, NIHR CLAHRC for
ASC is strongly biased towards males [7], with ratios of 4:1 Cambridgeshire and Peterborough. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
(male:female) for classic autism [8] and as high as 11:1 in
Competing Interests: The authors have declared that no competing interests
individuals with AS [9]. The specific factors responsible for the exist.
higher male prevalence in ASC remain unclear. ASC is not the
Abbreviations: ADHD, Attention Deficit and Hyperactivity Disorder; AQ, Autism
only neurodevelopmental condition more common among Spectrum Quotient; AS, Asperger Syndrome; ASC, Autism Spectrum Conditions;
males—a greater prevalence in males versus females is also seen CAIS, Complete Androgen Insensitivity Syndrome; CD, conduct disorder; CNV,
copy number variation; EMB, extreme male brain; EQ, Empathy Quotient; E-S,
Empathizing-Systemizing; fT, fetal testosterone; mPFC, medial prefrontal cortex;
Unsolved Mysteries discuss a topic of biological importance that is poorly nT, neonatal testosterone; POA, preoptic area; SQ, Systemizing Quotient; TS,
understood and in need of research attention. Turner Syndrome
* E-mail: sb205@cam.ac.uk

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 Table 1. Male biased sex ratios in other neurodevelopmental conditions.

1 Attention Deficit Hyperactivity Disorder (ADHD). The ratio of males to females with ADHD is high in clinic samples (up to 10:1) [106,107]. However, it
drops to 2:1 to 4:1 in community samples [108,109,110] and the majority of studies in adults show no significant effect of sex on prevalence [111]. This suggests
that the biased sex ratios observed in ADHD may result from referral bias rather than a biological mechanism.
2 Conduct Disorder (CD). Males are two to four times more likely to develop CD than females [112], though no sex difference was observed in the recent
NHANES study [110]. This discrepancy probably reflects the observation that while sex differences are not pronounced in adolescent-limited antisocial behavior,
the male:female ratio for early-onset, life-course-persistent antisocial behavior is 10:1 or greater [113].
3 Dyslexia/Reading Disability (RD). Early research suggested that there was a significant excess of males with RD, but this view has been challenged as
reflecting referral bias and subjective methods of assessment [114]. It is clear that ascertainment bias does inflate the true prevalence of RD in males, but a
review of existing studies suggests that there is a slightly skewed gender ratio, between 1.7 and 2.00 [115].
4 Specific Language Impairment (SLI). While many early studies reported a male biased sex ratio of between 2:1 and 3:1 [116] for SLI, it has been suggested
that this reflects ascertainment bias [114]. Epidemiological studies have identified equivalent numbers of males and females meeting diagnostic criteria [117] or
increased prevalence in females [118].
5 Tourette Syndrome (TS). TS shows a male to female ratio of between 4:1 and 6:1 [119]. It is notable that 50%–90% have comorbid ADHD, particularly in
clinic populations, which may contribute to the biased ratio.

doi:10.1371/journal.pbio.1001081.t001

autosomal penetrance theory (which posits that females harbor diagnosis (2–4 years) [21]. In addition, independent of global
fewer ASC-related mutations on autosomal chromosomes). Future differences in brain size, the amygdala in typical males tends to be
research will help to resolve the validity or flaws of these theories, larger than in females [22], and early in development the
which for now remain neither fully confirmed nor refuted. Here, amygdala in autism is even more enlarged than that observed in
we lay out some of the evidence for these theories in explaining the typical males [23–25]. In addition to such structural sexual
male bias in ASC. dimorphism in the brain, exaggeration of neural sexual dimor-
phism extends to brain function and corroborates predictions from
Is ACS an Extreme Expression of the Male Brain? the EMB theory (see Table 3 and Text S1 for fuller discussion)
[26–29].
The Extreme Male Brain (EMB) theory of autism extends the The set of striking findings of hyper-masculinization in ASC at
Empathizing-Systemizing (E-S) theory of typical sex differences three simultaneous levels (cognitive, neuroanatomy, and neural
[14], which proposes that females on average have a stronger drive function) raises the question as to which biological mechanism(s)
to empathize (to identify another person’s thoughts and feelings and are involved. Two plausible mechanisms that could give rise to
to respond to these with an appropriate emotion), while males on sexual dimorphism, hyper-masculinization, and/or the absence of
average have a stronger drive to systemize (to analyze or construct typical sexual dimorphism at the levels of brain, cognition, and
rule-based systems). Whilst sociologists still debate if there are any behavior are the ‘‘organizing’’ effects of fetal testosterone (fT) [30–
sex differences at all, and if so whether these are purely the result 32] and X- or Y-linked genetic factors. We review these three
of cultural conditioning, biologists have long known from animal interesting hypotheses, since these may also have relevance to the
research that sex differences in behavior exist in primates and are sex ratio in ASC. These are not proposed as complete explanations
influenced by biology as well as the environment. for ASC, since ASC is recognized to be multi-factorial, but they
On the Empathy Quotient (EQ) [15] typical females score may form an important part of the explanation.
higher than typical males who score higher than those with ASC
[15]. On the Systemizing Quotient (SQ), individuals with ASC What Might Cause an Extreme Male Brain?
score higher than typical males who score higher than typical
females [16–18]. Additional psychological evidence (summarized The Fetal Testosterone (fT) Theory
in Table 2 and in Text S1) shows that—irrespective of the Fetal androgens affect the brain: Evidence from animal
direction of sex difference—people with autism show an extreme and human studies. Animal studies, especially in rodents,
of the male profile. Note that the EMB theory does not state that confirm that early exposure to androgens (such as testosterone)
all psychological sex differences will be exaggerated in ASC—only acts on the brain to produce sex differences in behavior, cognition,
those relating to empathy and systemizing. brain structure, and function (see Text S1 for more discussion of
work with animals) [31–33]. It is widely accepted that fT exposure
Sexual Dimorphism in the Human Brain also affects brain development and behavior in humans. Human
Additional support for the EMB theory of ASC comes from males experience a surge in fT between weeks 8 to 24 of gestation
evidence of neural sexual dimorphism across development. Some [34–36], reaching almost pubertal levels. There is also a second
key examples of typical sexual dimorphism reveal an extreme of surge soon after birth (here called ‘‘neonatal testosterone,’’ or nT).
the typical male profile in the neurodevelopment of ASC [19]. Usually the levels remain high and then drop to barely detectable
However, one caveat to keep in mind is that just as all psychological levels by 4–6 months [37], until the third surge at puberty. Whilst
sex differences do not constitute an exaggerated form of maleness the third surge is understood to be controlling the onset of puberty,
in ASC, neither do all neural differences. Indeed, given that the the function of first surge (fT) is believed to play a major role in
EMB theory is defined at the psychological level, we should expect brain masculinization.
only a narrow set of neural sex differences will be involved in such While direct manipulation of hormones as has been conducted
hyper-masculinization in ASC. A key finding supporting this in animal studies is unquestionably unethical in human fetuses and
prediction is that infant males on average have a larger brain than infants, alternative research strategies include relating individual
females [20] and children with autism have even larger brains variation in amniotic fT exposure to later development [38], or
early in life right around the time they would typically receive a studying people in whom—for medical reasons—the sex hor-

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 Table 2. A summary of the psychological evidence for the Extreme Male Brain (EMB) theory (see Text S1 for a fuller discussion).

Psychological Measure Autism.Male.Female Female.Male.Autism Key References

Adolescent AQ 3 [120]
Adult Autism Spectrum Quotient (AQ) 3 [104,121–124]
Adult Systemizing Quotient (SQ) 3 [16]
Child AQ 3 [125]
Child SQ 3 [126]
Childhood Autism Spectrum Test (CAST) 3 [127–130]
Embedded Figures Test 3 [131,132]
Intuitive Physics Test 3 [133,134]
Social Responsiveness Scale 3 [135,136]
Quantitative Checklist for Autism in Toddlers (Q-CHAT) 3 [137]
Adult Empathy Quotient (EQ) 3 [15]
Child EQ 3 [126]
Faux Pas Test 3 [138]
Friendship and Relationship Questionnaire (FQ) 3 [139]
Reading the Mind in the Eyes 3 [140]
Social Stories Questionnaire (SSQ) 3 [133]

doi:10.1371/journal.pbio.1001081.t002

mones are higher or lower than expected for a person’s sex [39], Project, initiated by our group in 1998, children whose mothers
and using proxy measures of fT exposure. Here we review had amniocentesis during pregnancy (but who were otherwise
evidence from studies of cognitive traits relevant to ASC and their developing normally) have been followed up after birth every year
relationship with amniotic fT. (Evidence from disorders of sexual or two and are now approximately 11 years of age [34].
differentiation and from proxy measures of fT exposure is Evidence that amniotic fT affects individual differences in
presented in the Text S1.) cognitive development in typically developing children (but with
Fetal androgens affect ASC traits: evidence from amniotic clear relevance to ASC) includes the following: fT is inversely
fluid testosterone. fT can be measured in amniotic fluid, associated with frequency of eye contact at 12 months old [45] and
obtained during routine amniocentesis. Because amniocentesis is with size of vocabulary development at 18 and 24 months [46]. fT
typically performed during the second trimester of pregnancy is also inversely associated with quality of social relationships at 48
(usually 14–20 weeks of gestation), when serum testosterone peaks months [47] and with empathy at 48 and 96 months [48,49]. In
in male fetuses, it offers a unique opportunity to compare fT with contrast, amniotic fT is positively associated with narrow interests at
ASC traits. There is a well-documented large sex difference in 48 months [47], with ‘‘systemizing’’ at 96 months [18], and with
amniotic androgen levels [40–44]. The origin of androgens in performance on the Embedded Figures Test (EFT) as a measure of
amniotic fluid appears to be the fetus itself, and testosterone attention to detail at 96 months [50]. These are all behaviors that
obtained in amniotic fluid is thought to be a good reflection of the show sexual dimorphism, but critically, these fT effects are often
levels in the fetus [38]. In the Cambridge Fetal Testosterone found within one sex as well as when analyzing the sexes

Table 3. A summary of the evidence consistent with the EMB theory at the neural level (see Text S1 for a fuller discussion).

Brain Region Autism.Male.Female Female.Male.Autism Key References

Structure
Total brain volume 3 [20,141–143]
Amgydala 3 [22–25,144–150].
Corpus callosum 3 [151,152]
Perisylvian language areas (Heschl’s 3 [22,153–156]
gyrus/planum temporale)
L.R asymmetry in planum temporale 3 [22,154,157–160]
Lateral fronto-parietal cortex 3 [144,145,147,150,156,161–165]
Function
Default Mode Network Connectivity 3 [166,167]
Embedded Figures fMRI 3 [27–29,168]
Reading the Mind in the Eyes task fMRI 3 [26,28]

doi:10.1371/journal.pbio.1001081.t003

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combined. The finding of a consistent inverse correlation between Although some studies have failed to support a role for
fT and social domains, and a consistent positive correlation testosterone in ASC (and most of these have not been able to
between fT and non-social domains, across development, is study fT specifically), the studies reported above suggest that fT is
striking and suggests these are real effects which substantiate the implicated in the biased sex ratio seen in ASC. However,
notion that fT plays an ‘‘organizational’’ role in development. alternative models exist which could also explain the excess of
In the first study to directly assess if fT affects not just human males with ASC. In the final part of this article we review the main
cognition but also human brain structure, we found that increasing contender, the X chromosome theory. For completeness, we also
levels of fT are associated with increasing rightward asymmetry in briefly review the Y chromosome theory and the reduced
the thickness of one subsection of the corpus callosum, the isthmus autosomal penetrance theory.
[51]. This is interesting since the isthmus projects to posterior
parietal and superior temporal cortices, which are integral for The X Chromosome Theory
language and visuospatial ability and are known to be sexually The X chromosome contains more genes expressed in the brain
dimorphic in lateralization, structure, and function (see Text S1). than the other chromosomes [54]. In addition, more than 10% of
All of the above behavioral domains (eye contact, language people with learning difficulties show an X-linked pattern of
development, quality of social relationships, narrow interests, inheritance [55], involving mutations in over 90 different X-linked
empathy, systemizing, and embedded figures/attention to detail) genes [56,57]. Individuals with X-linked learning difficulties may
and brain structure show sexual dimorphism and appear hyper- also have ASC, the best-known example being Fragile X
masculinized in ASC, raising the possibility that fT may play a role Syndrome, where 46% of males and 16% of females carrying
in the development of ASC itself. Three recent experiments have the full mutation also have ASC [58].
confirmed a positive correlation between fT levels and the number On the face of it, the biased sex ratio in ASC would therefore be
of autistic traits a child shows in toddlerhood [52] and in later parsimoniously explained by an X chromosome theory. A problem
childhood [53]. The Cambridge Fetal Testosterone Project has too for this theory is that the majority of linkage and association
few children (currently n = 635 are enrolled) to test whether fT is studies of ASC have failed to find regions of interest on the X
elevated in those who later are diagnosed with ASC, but testing for chromosome [59–72]. A related problem for this theory is that in
a direct association between fT levels and diagnosed ASC will be the three recent genome-wide studies of copy number variation
possible in our ongoing collaboration with the Danish Biobank, (CNV) in individuals with ASC that identified mutations affecting
which has tens of thousands of amniotic samples, with adequate the X chromosome, this was only true in a very small minority of
power to test this hypothesis. Using a different line of evidence, a cases. This suggests X-linked mutations are only occasionally seen
number of studies have found also current androgen dysregulation in ASC and therefore cannot account for the large majority of
in ASC or in their relatives, or androgen-related genes being cases. A final problem for the X-linked theory is that other large
associated with ASC (see Table 4 for a summary of the evidence CNV scans have reported no significant findings on the X
for the fT/androgen theory). chromosome [67,73–75]. While epigenetic effects on X chromo-

Table 4. Evidence for the effect of sex steroids in autism (see Text S1 for a fuller discussion).

Evidence Key References

From typically developing children

Eye contact is inversely related to fT [45]
Quality of social relationships are inversely related to fT [47]
Vocabulary size is inversely related to fT [46]
Empathy is inversely related to fT [48,49]
Autistic traits are positively associated with fT [52,53]
Restricted interests are positively associated with fT [47]
Systemizing is positively associated with fT [18]
Rightward asymmetry in the isthmus of the corpus callosum is positively associated with fT [51]
From people with ASC
10 genes involved in sex steroid synthesis, transport, and/or metabolism associated with AS or AQ or empathy: [169]
HSD11B1, LHCGR, CYP17A1, CYP19A1, SCP2, CYP11B1, ESR1, ESR2, HSD17B4, HSD17B2
Timing of puberty: Boys with ASC enter puberty earlier. Girls with ASC enter puberty later [170–172]
Testosterone related medical conditions in women with ASC and their mothers (e.g., PCOS, breast and ovarian cancers, acne) [172]
Testosterone related characteristics in women with ASC and their mothers [172,173]
Lower 2D:4D ratio in ASC, and parents [174–176]
SRD5A1 and AR genes associated with ASC [177,178]
Decreased expression of RORA gene and aromatase in post-mortem frontal and cerebellar tissue [179,180]
Females with Congenital Adrenal Hyperplasia (CAH) have elevated AQ [181]
Testosterone levels are elevated in ASC [182]
Androstenedione levels are elevated in ASC [183]

doi:10.1371/journal.pbio.1001081.t004

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some genes could affect risk for autism, this hypothesis has not yet a study of the whole brain in a mouse model of TS did not identify
been empirically tested. In summary, at present it appears that any paternally expressed X-linked genes, but did identify a
there are X-linked causes of ASC, but these represent a far smaller maternally expressed gene, xlr3b, which was implicated in
percentage of cases than is seen in learning difficulties. cognitive flexibility [87]. However, it is unclear if a functioning
Girls with Turner Syndrome (TS) (characterized by the XO human orthologue of this gene exists.
karyotype) [76] are at an increased risk for ASC, which could be A recent study searched for imprinted genes in the preoptic area
the result of an X-linked recessive gene, but this is not clear-cut (POA) and medial prefrontal cortex (mPFC) in mouse. No X-
since XYY and XXYY males are also at increased risk [77]. One linked imprinted genes were identified when using a cut-off of
study [78] has also reported higher autistic traits scores (as p,0.05, but using a less stringent cut-off of 0.1, a small set of
measured on the Autism Spectrum Quotient [AQ] in XXY males), putative X-linked imprinted genes were identified including three
though this is not always seen [77]. paternally expressed genes in the POA and three different
There are other possible versions of the X chromosome theory paternally expressed genes in the mPFC [88]. Three of these
of ASC. Although females have two X chromosomes, only one of genes (cask, acsl4, and ids) have human orthologues whose
these is generally active. X chromosome inactivation (the process by disruption can cause MR. Another intriguing finding from this
which one X chromosome is suppressed while the other remains study was that total levels of expression from Xm were increased
active) acts to negate the ‘‘dosage’’ difference in X chromosome relative to those of Xp in females. This could reflect preferential
genes between males and females. However, 10%–15% of X inactivation of the Xp and would act to minimize dosage
chromosome genes may continue to be expressed from the differences between the sexes. If a screen of females with ASC
supposedly inactive X. Gong and colleagues [79] directly tested identified rare mutations or CNVs on the Xp, this would provide
this hypothesis and found no evidence for a skewed X important evidence for the theory.
chromosome inactivation in a large sample of individuals with
and without ASC. X chromosome gene dosage could play a role in The Y Chromosome Theory
sex ratios if the non-silenced genes were protective. However, Since the XYY and XXYY syndromes have an increased
comparing the incidence of ASC across different sex aneuploidies incidence of ASC [89–91], it is important to consider if the male
does not suggest a simple dosage effect, and frequently the ASC bias in ASC could also result from the male-limited expression of
occurs in the context of clear learning disabilities, and so could genes on the Y chromosome. This possibility has attracted very
simply be secondary to the latter. It is increasingly recognized that little research attention. Such genes should be located in the non-
learning difficulties are themselves a risk factor for ASC [80], so recombining region of the Y. SRY (the sex determining gene) is
any evaluation of the X chromosome theory needs to consider expressed in the medial rostral hypothalamus, as well as the frontal
these separately. and temporal regions of the human brain [92]. In vitro assays
Genomic imprinting (the process by which genetic effects are suggest that SRY can increase transcription of tyrosine hydroxylase
influenced by whether the genes are transmitted through the (the rate-limiting enzyme in dopamine biosynthesis) by binding at
father or the mother [81]) is also of interest. Ordinarily this would a promoter site [93]. In addition, the knockdown of SRY
not result in sex differences in the rate of a condition, but could do expression in the substantia nigra of the rat decreases tyrosine
so if the imprinting affects the X chromosome. Skuse [82,83] hydroxylase expression [94]. This could implicate SRY in the male
suggested that an imprinted X-locus could explain sex differences bias for disorders involving disregulated catecholamines such as
in social and communication skills and the male vulnerability to ADHD. SRY may also regulate the monoamine oxidase A (MAO-
social and communication impairment. His theory was inspired by A) gene [95]. Other Y-linked genes known to be expressed in
the finding that in individuals with TS, the rate of social difficulties human brain include ZFY and PCDH11Y [92,96].
varied according to whether their single X chromosome was A small candidate gene study failed to find associations between
inherited from the father (XpO cases) or the mother (XmO cases) variants in PCDH11Y and autism [96], while ZFY has not been
(where p is paternal, and m is maternal) [82]. Social problems are specifically investigated. One study has reported a missense variant
greater in XmO relative to XpO individuals. Typical females in NLGN4Y in a single patient with autism and his father with
always inherit an X chromosome from both parents (XpXm), but learning difficulties [97]. Comparison of Y chromosome haplotype
typical males always have only a maternal X (XmY). Skuse groups between cases and controls represents an alternative
hypothesized that a gene expressed on the paternal X acts as a strategy to identifying Y chromosome effects. Two such studies
protective factor against the social problems seen in TS and, by have been conducted in regard to ASC—one was positive [98] and
extrapolation, as a protective factor against ASC. one was negative [99]. Y chromosome effects certainly merit
Creswell and colleagues [84] subsequently reported five cases of additional research attention, but current evidence is too sparse to
ASC from an unselected sample of 150 subjects with TS. All the evaluate to what extent this mechanism could explain the sex bias
cases were XmO (or had a structurally abnormal paternal X). All in ASC.
of the cases in that report also had moderate to severe learning
difficulties and low verbal IQ scores, despite the fact that Reduced Autosomal Penetrance in Females? A Final
intelligence is usually in the average range in TS. This raises the Theory
possibility that the kind of ASC observed was related to learning For completeness we briefly mention a final theory, arising from
difficulties (i.e., applicable only to classic autism rather than the full studies of rare CNVs with ASC [67,74,100,101]. As mentioned
autistic spectrum, which includes AS). Also, given that 77% of TS earlier, these scans have not routinely implicated the X
females are XmO, while only 23% are XpO [85], this means that chromosome, but this final model proposes that a significant
by chance one would expect to find ASC more often associated with proportion of ASC cases are the result of dominant de novo
XmO than with XpO. mutations (on the autosomes) which have reduced penetrance in
No specific X-linked genes have yet been identified which females. Statistical analysis of ASC family data has provided
explain these findings, but there is evidence that whichever genes supporting evidence [102]. A problem for this theory, however, is
are involved may modulate amygdala circuits which are disrupted that the majority of studies report that the sex ratio in children
in ASC [86]. Whilst the amygdala has not been directly examined, with ASC and de novo CNVs is 1:1. This clearly does not fit with

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 Table 5. Rates of ASC/autistic traits in different medical conditions, as predicted by the X and Y chromosome theories, and the fT
theory.

Prediction from X-Dosage or Prediction from Prediction from Y- Prediction from FT

Medical Condition X-Linked Recessive Model Imprinted X Model Chromosome Model Theory

Complete Androgen Insensitivity Similar to typical males Similar to typical males Similar to typical males Similar to typical females
Syndrome (CAIS) in males
Congenital Adrenal Hyperplasia Similar to typical females Similar to typical females Similar to typical females Similar to typical males
(CAH) in females
Turner Syndrome (with a Similar to typical males Similar to typical males Similar to typical females Similar to typical females
maternal X; XmO)
Turner Syndrome (with a Similar to typical males Similar to typical females Similar to typical females Similar to typical females
paternal X; XpO)

doi:10.1371/journal.pbio.1001081.t005

reduced penetrance in females [103]. A second problem for this more research because presenting them as independent ignores the
theory is that it does not address why penetrance should be reduced fact that both are related to fT. Nor can we yet extrapolate the fT
in females. However, we agree that it is critical that large-scale results to individuals with an ASC diagnosis since this will require
linkage and association studies test for sex-specific effects. much larger collections of amniotic samples than has been possible
to date. Strengthening a role for fT in ASC is the recent genetic
Not Mutually Exclusive Theories evidence in which SNPs in key sex steroid genes are associated
The X and Y chromosome theories and the fT model offer with either diagnosed AS and/or autistic traits.
potential explanations for the biased sex ratio in ASC and warrant
further research. While often conceived as competing theories,
they need not be mutually exclusive. This is because we cannot Box 1. fT and X-linked factors in other neurodevelop-
rule out the possibility that genes on the X and Y chromosomes mental conditions.
may be regulated by fT or have products that affect the production ADHD: fT has been implicated by several studies using
or sensitivity of an individual to fT. X chromosome genes may also the proxy measure of 2D:4D (finger) ratio [176,184,185]
regulate Y chromosome genes and vice versa. In addition, it is and one study of genetic variation at the androgen
possible that X or Y chromosome genes and fT exposure are receptor [186]. An animal model of ADHD suggests that
independent risk factors for ASC. early androgen exposure affects catecholamine innerva-
The theories do, however, make contrasting predictions for tion of the frontal cortex and cognitive function [187].
ADHD has also been associated with X-linked genes, in
individuals with certain intersex conditions, in particular those
particular monoamine oxidase-B [188,189] and steroid
with Complete Androgen Insensitivity Syndrome (CAIS), where
sulfatase [190]. The latter has also been implicated in
there is a complete deficiency of working androgen receptors, in attention deficits in a mouse model of Turner Syndrome
the presence of a typical male genetic complement (XY). Given the [191]. However, genome-wide scans have not implicated
rarity of this condition, studies using measures of autistic traits the X chromosome in ADHD [192,193].
(such as the AQ [104]) may be more feasible than studies of Conduct Disorder (CD): Activational effects of gonadal
diagnosed cases of ASC in CAIS per se. (These contrasting steroids have shown relationships with CD [194–196], but
predictions are summarized in Table 5.) there is not a simple one-to-one correspondence. In
Finally, whilst it may be that the psychiatric classification system addition, the X-linked gene coding for monoamine oxidase
is ‘‘carving nature at its joints,’’ it is also possible that some of the A has been linked to aggression and neural hyperactivity
underlying hormonal and genetic mechanisms are involved not to threat [197].
just in ASC but are relevant to a broader category of Reading Disorder/Dyslexia: Two studies have failed to
neurodevelopmental conditions (see Box 1). find a relation between 2D:4D (digit) ratio (as a proxy for
fT) and dyslexia [115,198]. One genome-wide linkage
analysis suggested a locus on Xq26 [199]. A nearby
Looking Ahead: Toward a Unified Theory?
susceptibility locus in a single extended family has also
For as long as ASC has been recognized, a higher prevalence been reported [198].
has been observed in males, yet until 1997, when our group Specific Language Impairment: The correlation be-
proposed the extreme male brain theory, this potential clue to the tween amniotic fT levels and early vocabulary [46,200]
etiology of the condition went unexplored [105]. In the early years could indicate a role for fT in SLI. Genome-wide linkage
following the publication of the EMB theory, the majority of the studies have not implicated the X chromosome [201–203].
evidence relevant to the theory came from psychological studies, Tourette Syndrome: Tics in individuals with TS increase
in intensity during puberty, suggesting an activational
but since 2001 supporting evidence has also come from biology.
testosterone effect. A role for fT has also been proposed
In the present article we have considered studies that suggest based on a study of gender dysphoria, play preferences,
that fetal testosterone is involved in sex differences in key areas of and spatial skills in individuals with TS [204]. Genome-wide
behavior and cognition in the general population (in social linkage studies have not implicated the X chromosome
development, language development, empathy, systemizing, and [205], but Lawson-Yuen [206] have reported a pedigree
attention to detail), as well as in influencing brain structure, and with a NLGN4X deletion which was associated with TS in
the number of autistic traits an individual possesses. Understand- one family-member.
ing the relationship between empathy and systemizing will require

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 The main alternatives to the fT theory are the X and Y relating prenatal hormones to masculinization of the mind and the
chromosome theories. Future research could usefully test these brain.
theories against each other, or test if all are valid, either
independently or because of gene-hormone interactions. Whilst Supporting Information
it remains a possibility that the male bias in ASC simply reflects
diagnostic difficulties in recognizing ASC in females, the link Text S1 Supplementary material.
between ASC and maleness has generated a novel framework for (DOC)
exploring the link between sex and ASC, and a wealth of data

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