Why Are Autism Spectrum Conditions More Prevalent in Males?

25 Pages·2011·4.99 MB·English

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
1AutismResearchCentre,DepartmentofPsychiatry,UniversityofCambridge,Cambridge,UnitedKingdom,2CentreforIntegrativeNeuroscienceandNeurodynamics,
SchoolofPsychologyandClinicalLanguageSciences,UniversityofReading,Reading,UnitedKingdom,3DepartmentofPsychiatry,UniversityofNorthCarolina–Chapel
Hill,ChapelHill,NorthCarolina,UnitedStatesofAmerica
inAttentionDeficitandHyperactivityDisorder(ADHD),dyslexia,
Abstract: Autism Spectrum Conditions (ASC) are much conduct disorder (CD), specific language impairment, Tourette
morecommoninmales,abiasthatmayoffercluestothe Syndrome, andLearning Difficulties (seeTable 1) [10].
etiologyofthiscondition.Althoughthecauseofthisbias
However, the male bias is much more pronounced in ASC,
remainsamystery,wearguethatitoccursbecauseASCis
especiallyinthecaseofAS.Thismalebiascouldsimplyreflectthe
anextrememanifestationofthemalebrain.Theextreme
difficulty of diagnosing AS in females. Though classic autism
male brain (EMB) theory, first proposed in 1997, is an
wouldnotbemissedinfemales,AScouldbeifitpresentedassome
extension of the Empathizing-Systemizing (E-S) theory of
other condition, such as anorexia [11] or borderline personality
typical sex differences that proposes that females on
disorder [12], both of which involve the exercise of excessive
average have a stronger drive to empathize while males
controlovertheenvironmentorotherpeople,andacertaindegree
onaveragehaveastrongerdrivetosystemize.Inthisfirst
major update since 2005, we describe some of the of a self-centeredness. Equally, AS in females could be under-
evidencerelatingtotheEMBtheoryofASCandconsider diagnosed if females are more motivated to learn to conform
how typical sex differences in brain structure may be sociallyorhavebetterimitationskillsthatallowthemto‘‘pretend
relevant to ASC. One possible biological mechanism to to be normal’’ [13]. Finally, this male bias might reflect the
accountforthemalebiasistheeffectoffetaltestosterone inability of the widely used diagnostic instruments (the Autism
(fT).Wealsoconsideralternativebiologicaltheories,theX Diagnostic Observation Schedule (ADOS) or Autism Diagnostic
andYchromosometheories,andthereducedautosomal Interview-Revised (ADI-R)) to detect the more subtle ways in
penetrance theory. None of these theories has yet been whichASmay presentin females.
fullyconfirmedorrefuted,thoughtheweightofevidence 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
physiologicalattributesofthemalebrain;thatis,malesneedonly
pathways). Ultimately, as these theories are not mutually
slight psychological and physiological changes to exhibit ASC
exclusiveandASCismulti-factorial,theymayhelpexplain
while females would require more, thus making ASC rarer in
the male prevalenceofASC.
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? possibilitiesincludetheX-andY-linkedtheoriesandthereduced
The diagnosis of classic autism and Asperger Syndrome (AS),
knownasAutismSpectrumConditions(ASC),restsondifficulties Citation:Baron-CohenS,LombardoMV,AuyeungB,AshwinE,ChakrabartiB,
etal.(2011)WhyAreAutismSpectrumConditionsMorePrevalentinMales?PLoS
in reciprocal social interaction and communication, alongside
Biol9(6):e1001081.doi:10.1371/journal.pbio.1001081
strongly repetitive behavior and unusually narrow interests [1].
PublishedJune14,2011
TheprevalenceofASCisestimatedtobe1%[2,3].Adiagnosisof
classic autism, unlike AS, also requires thepresence of additional Copyright: ! 2011Baron-Cohenetal.Thisisanopen-accessarticledistributed
learning difficulties and language delay. ASC is neurobiological, under the terms of the Creative Commons Attribution License, which permits
evidencedbyatypicalbraindevelopmentinstructureandfunction unrestricted use, distribution, and reproduction in any medium, provided the
originalauthorandsourcearecredited.
[4].ASCisalsogenetic[5,6]thoughnotwithoutsomeinteraction
with environmental influences. Funding:MRC,WellcomeTrust,NancyLurieMarksFoundation,NIHRCLAHRCfor
ASC is strongly biased towards males [7], with ratios of 4:1 CambridgeshireandPeterborough.Thefundershadnoroleinstudydesign,data
collectionandanalysis,decisiontopublish,orpreparationofthemanuscript.
(male:female) for classic autism [8] and as high as 11:1 in
individuals with AS [9]. The specific factors responsible for the CompetingInterests:Theauthorshavedeclaredthatnocompetinginterests
exist.
higher male prevalence in ASC remain unclear. ASC is not the
only neurodevelopmental condition more common among Abbreviations:ADHD,AttentionDeficitandHyperactivityDisorder;AQ,Autism
SpectrumQuotient;AS,AspergerSyndrome;ASC,AutismSpectrumConditions;
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,fetaltestosterone;mPFC,medialprefrontalcortex;
Unsolved Mysteries discuss a topic of biological importance that is poorly nT, neonatal testosterone; POA, preoptic area; SQ, Systemizing Quotient; TS,
understoodandinneedofresearchattention. TurnerSyndrome
*E-mail:[email protected]
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Table1. Malebiased sex ratiosin otherneurodevelopmentalconditions.
1 AttentionDeficitHyperactivityDisorder(ADHD).TheratioofmalestofemaleswithADHDishighinclinicsamples(upto10:1)[106,107].However,it
dropsto2:1to4:1incommunitysamples[108,109,110]andthemajorityofstudiesinadultsshownosignificanteffectofsexonprevalence[111].Thissuggests
thatthebiasedsexratiosobservedinADHDmayresultfromreferralbiasratherthanabiologicalmechanism.
2 ConductDisorder(CD).MalesaretwotofourtimesmorelikelytodevelopCDthanfemales[112],thoughnosexdifferencewasobservedintherecent
NHANESstudy[110].Thisdiscrepancyprobablyreflectstheobservationthatwhilesexdifferencesarenotpronouncedinadolescent-limitedantisocialbehavior,
themale:femaleratioforearly-onset,life-course-persistentantisocialbehavioris10:1orgreater[113].
3 Dyslexia/ReadingDisability(RD).EarlyresearchsuggestedthattherewasasignificantexcessofmaleswithRD,butthisviewhasbeenchallengedas
reflectingreferralbiasandsubjectivemethodsofassessment[114].ItisclearthatascertainmentbiasdoesinflatethetrueprevalenceofRDinmales,buta
reviewofexistingstudiessuggeststhatthereisaslightlyskewedgenderratio,between1.7and2.00[115].
4 SpecificLanguageImpairment(SLI).Whilemanyearlystudiesreportedamalebiasedsexratioofbetween2:1and3:1[116]forSLI,ithasbeensuggested
thatthisreflectsascertainmentbias[114].Epidemiologicalstudieshaveidentifiedequivalentnumbersofmalesandfemalesmeetingdiagnosticcriteria[117]or
increasedprevalenceinfemales[118].
5 TouretteSyndrome(TS).TSshowsamaletofemaleratioofbetween4:1and6:1[119].Itisnotablethat50%–90%havecomorbidADHD,particularlyin
clinicpopulations,whichmaycontributetothebiasedratio.
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
fewerASC-relatedmutationsonautosomalchromosomes).Future differencesinbrainsize,theamygdalaintypicalmalestendstobe
researchwillhelptoresolvethevalidityorflawsofthesetheories, 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
welayoutsomeoftheevidenceforthesetheoriesinexplainingthe typical males [23–25]. In addition to such structural sexual
male biasin ASC. dimorphism in the brain, exaggeration of neural sexual dimor-
phismextendstobrainfunctionandcorroboratespredictionsfrom
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 Thesetofstrikingfindingsofhyper-masculinizationinASCat
Empathizing-Systemizing (E-S) theory of typical sex differences three simultaneous levels (cognitive, neuroanatomy, and neural
[14],whichproposesthatfemalesonaveragehaveastrongerdrive
function) raises the question as to which biological mechanism(s)
toempathize(toidentifyanotherperson’sthoughtsandfeelingsand
are involved. Two plausible mechanisms that could give rise to
torespondtothesewithanappropriateemotion),whilemaleson
sexualdimorphism,hyper-masculinization,and/ortheabsenceof
average have astronger drive to systemize(to analyze or construct
typical sexual dimorphism at the levels of brain, cognition, and
rule-basedsystems).Whilstsociologistsstilldebateifthereareany
behaviorarethe‘‘organizing’’effectsoffetaltestosterone(fT)[30–
sexdifferencesatall,andifsowhetherthesearepurelytheresult
32] and X- or Y-linked genetic factors. We review these three
of cultural conditioning, biologists have long known from animal
interestinghypotheses,sincethesemayalsohaverelevancetothe
researchthatsexdifferencesinbehaviorexistinprimatesandare
sexratioinASC.Thesearenotproposedascompleteexplanations
influenced bybiology aswell astheenvironment.
for ASC, since ASC is recognized to be multi-factorial, but they
On the Empathy Quotient (EQ) [15] typical females score mayforman important part oftheexplanation.
higher than typical males whoscore 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,
ofthemaleprofile.NotethattheEMBtheorydoesnotstatethat confirm that early exposure to androgens (such as testosterone)
allpsychologicalsexdifferenceswillbeexaggeratedinASC—only actsonthebraintoproducesexdifferencesinbehavior,cognition,
those relating toempathy andsystemizing. brain structure, and function (see Text S1 for more discussion of
workwithanimals)[31–33].ItiswidelyacceptedthatfTexposure
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 malesexperienceasurgeinfTbetweenweeks8to24ofgestation
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 surgesoonafterbirth(herecalled‘‘neonataltestosterone,’’ornT).
the typical male profile in the neurodevelopment of ASC [19]. Usuallythelevelsremainhighandthendroptobarelydetectable
However,onecaveattokeepinmindisthatjustasallpsychological levelsby4–6months[37],untilthethirdsurgeatpuberty.Whilst
sexdifferencesdonotconstituteanexaggeratedformofmaleness thethirdsurgeisunderstoodtobecontrollingtheonsetofpuberty,
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
EMBtheoryisdefinedatthepsychologicallevel,weshouldexpect brain masculinization.
onlyanarrowsetofneuralsexdifferenceswillbeinvolvedinsuch Whiledirectmanipulationofhormonesashasbeenconducted
hyper-masculinization in ASC. A key finding supporting this inanimalstudiesisunquestionablyunethicalinhumanfetusesand
predictionisthatinfantmalesonaveragehavealargerbrainthan 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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Table2.AsummaryofthepsychologicalevidencefortheExtremeMaleBrain(EMB)theory(seeTextS1forafullerdiscussion).
PsychologicalMeasure Autism.Male.Female Female.Male.Autism KeyReferences
AdolescentAQ 3 [120]
AdultAutismSpectrumQuotient(AQ) 3 [104,121–124]
AdultSystemizingQuotient(SQ) 3 [16]
ChildAQ 3 [125]
ChildSQ 3 [126]
ChildhoodAutismSpectrumTest(CAST) 3 [127–130]
EmbeddedFiguresTest 3 [131,132]
IntuitivePhysicsTest 3 [133,134]
SocialResponsivenessScale 3 [135,136]
QuantitativeChecklistforAutisminToddlers(Q-CHAT) 3 [137]
AdultEmpathyQuotient(EQ) 3 [15]
ChildEQ 3 [126]
FauxPasTest 3 [138]
FriendshipandRelationshipQuestionnaire(FQ) 3 [139]
ReadingtheMindintheEyes 3 [140]
SocialStoriesQuestionnaire(SSQ) 3 [133]
doi:10.1371/journal.pbio.1001081.t002
mones are higher or lower than expected fora 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
evidencefromstudiesofcognitivetraitsrelevanttoASCandtheir developingnormally)havebeenfollowedupafterbirtheveryyear
relationship with amniotic fT. (Evidence from disorders of sexual or twoandarenowapproximately 11years of age[34].
differentiation and from proxy measures of fT exposure is Evidence that amniotic fT affects individual differences in
presented intheTextS1.) cognitive development in typically developing children (but with
FetalandrogensaffectASCtraits:evidencefromamniotic clear relevance to ASC) includes the following: fT is inversely
fluid testosterone. fT can be measured in amniotic fluid, associatedwithfrequencyofeyecontactat12monthsold[45]and
obtained during routine amniocentesis. Because amniocentesis is withsizeofvocabularydevelopmentat18and24months[46].fT
typically performed during the second trimester of pregnancy is also inversely associated with quality of social relationships at 48
(usually14–20weeksofgestation),whenserumtestosteronepeaks months [47] and with empathy at 48 and 96 months [48,49]. In
inmalefetuses,itoffersauniqueopportunitytocomparefTwith contrast,amnioticfTispositivelyassociatedwithnarrowinterestsat
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 performanceontheEmbeddedFiguresTest(EFT)asameasureof
amniotic fluid appears to be the fetus itself, and testosterone attentiontodetailat96months[50].Theseareallbehaviorsthat
obtainedinamnioticfluidisthoughttobeagoodreflectionofthe 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
Table3. Asummary ofthe evidenceconsistent with the EMBtheoryat theneural level(see TextS1 forafuller discussion).
BrainRegion Autism.Male.Female Female.Male.Autism KeyReferences
Structure
Totalbrainvolume 3 [20,141–143]
Amgydala 3 [22–25,144–150].
Corpuscallosum 3 [151,152]
Perisylvianlanguageareas(Heschl’s 3 [22,153–156]
gyrus/planumtemporale)
L.Rasymmetryinplanumtemporale 3 [22,154,157–160]
Lateralfronto-parietalcortex 3 [144,145,147,150,156,161–165]
Function
DefaultModeNetworkConnectivity 3 [166,167]
EmbeddedFiguresfMRI 3 [27–29,168]
ReadingtheMindintheEyestaskfMRI 3 [26,28]
doi:10.1371/journal.pbio.1001081.t003
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combined.Thefindingofaconsistentinversecorrelationbetween 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 studyfTspecifically),thestudiesreportedabovesuggestthatfTis
striking and suggests these are real effects which substantiate the implicated in the biased sex ratio seen in ASC. However,
notion that fT playsan ‘‘organizational’’ roleindevelopment. alternative models exist which could also explain the excess of
In the first study to directly assess if fT affects not just human maleswithASC.Inthefinalpartofthisarticlewereviewthemain
cognitionbutalsohumanbrainstructure,wefoundthatincreasing contender, the X chromosome theory. For completeness, we also
levelsoffTareassociatedwithincreasingrightwardasymmetryin briefly review the Y chromosome theory and the reduced
thethicknessofonesubsectionofthecorpuscallosum,theisthmus 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 TheXchromosomecontainsmoregenesexpressedinthebrain
dimorphic inlateralization, structure, andfunction(see TextS1). thantheotherchromosomes[54].Inaddition,morethan10%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],involvingmutationsinover90differentX-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
masculinizedinASC,raisingthepossibilitythatfTmayplayarole Syndrome, where 46% of males and 16% of females carrying
inthedevelopmentofASCitself.Threerecentexperimentshave thefull mutation alsohave ASC[58].
confirmedapositivecorrelationbetweenfTlevelsandthenumber Onthefaceofit,thebiasedsexratioinASCwouldthereforebe
of autistic traits a child shows in toddlerhood [52] and in later parsimoniouslyexplainedbyanXchromosometheory.Aproblem
childhood[53].TheCambridgeFetalTestosteroneProjecthastoo 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
elevatedinthosewholaterarediagnosedwithASC,buttestingfor chromosome[59–72].Arelatedproblemforthistheoryisthatin
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)inindividualswithASCthatidentifiedmutationsaffecting
which has tens of thousands of amniotic samples, with adequate theXchromosome,thiswasonlytrueinaverysmallminorityof
powertotestthishypothesis.Usingadifferentlineofevidence,a cases.ThissuggestsX-linkedmutationsareonlyoccasionallyseen
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 thefT/androgentheory). chromosome [67,73–75]. While epigenetic effects on X chromo-
Table4. Evidenceforthe effectof sexsteroids inautism(see TextS1 forafuller discussion).
Evidence KeyReferences
Fromtypicallydevelopingchildren
EyecontactisinverselyrelatedtofT [45]
QualityofsocialrelationshipsareinverselyrelatedtofT [47]
VocabularysizeisinverselyrelatedtofT [46]
EmpathyisinverselyrelatedtofT [48,49]
AutistictraitsarepositivelyassociatedwithfT [52,53]
RestrictedinterestsarepositivelyassociatedwithfT [47]
SystemizingispositivelyassociatedwithfT [18]
RightwardasymmetryintheisthmusofthecorpuscallosumispositivelyassociatedwithfT [51]
FrompeoplewithASC
10genesinvolvedinsexsteroidsynthesis,transport,and/ormetabolismassociatedwithASorAQorempathy: [169]
HSD11B1,LHCGR,CYP17A1,CYP19A1,SCP2,CYP11B1,ESR1,ESR2,HSD17B4,HSD17B2
Timingofpuberty:BoyswithASCenterpubertyearlier.GirlswithASCenterpubertylater [170–172]
TestosteronerelatedmedicalconditionsinwomenwithASCandtheirmothers(e.g.,PCOS,breastandovariancancers,acne) [172]
TestosteronerelatedcharacteristicsinwomenwithASCandtheirmothers [172,173]
Lower2D:4DratioinASC,andparents [174–176]
SRD5A1andARgenesassociatedwithASC [177,178]
DecreasedexpressionofRORAgeneandaromataseinpost-mortemfrontalandcerebellartissue [179,180]
FemaleswithCongenitalAdrenalHyperplasia(CAH)haveelevatedAQ [181]
TestosteronelevelsareelevatedinASC [182]
AndrostenedionelevelsareelevatedinASC [183]
doi:10.1371/journal.pbio.1001081.t004
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somegenescouldaffectriskforautism,thishypothesishasnotyet astudyofthewholebraininamousemodelofTSdidnotidentify
been empirically tested. In summary, at present it appears that any paternally expressed X-linked genes, but did identify a
thereareX-linkedcausesofASC,buttheserepresentafarsmaller maternally expressed gene, xlr3b, which was implicated in
percentage of cases than isseen inlearning difficulties. cognitive flexibility [87]. However, it is unclear if a functioning
Girls with Turner Syndrome (TS) (characterized by the XO human orthologue of thisgeneexists.
karyotype) [76] areat an increased riskfor ASC,whichcould be Arecentstudysearchedforimprintedgenesinthepreopticarea
the result of an X-linked recessive gene, but this is not clear-cut (POA) and medial prefrontal cortex (mPFC) in mouse. No X-
sinceXYYandXXYYmalesarealsoatincreasedrisk[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
measuredontheAutismSpectrumQuotient[AQ]inXXYmales), putativeX-linkedimprintedgeneswereidentifiedincludingthree
though thisisnot always seen [77]. paternally expressed genes in the POA and three different
ThereareotherpossibleversionsoftheXchromosometheory paternally expressed genes in the mPFC [88]. Three of these
ofASC.AlthoughfemaleshavetwoXchromosomes,onlyoneof 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 identifiedraremutationsorCNVsontheXp,thiswouldprovide
this hypothesis and found no evidence for a skewed X important evidenceforthetheory.
chromosome inactivation in a large sample of individuals with
andwithoutASC.Xchromosomegenedosagecouldplayarolein The Y Chromosome Theory
sex ratios if the non-silenced genes were protective. However, Since the XYY and XXYY syndromes have an increased
comparingtheincidenceofASCacrossdifferentsexaneuploidies incidence of ASC[89–91], itisimportant toconsider ifthe male
does not suggest a simple dosage effect, and frequently the ASC biasinASCcouldalsoresultfromthemale-limitedexpressionof
occurs in the context of clear learning disabilities, and so could genes on the Y chromosome. This possibility has attracted very
simplybesecondarytothelatter.Itisincreasinglyrecognizedthat littleresearchattention.Suchgenesshouldbelocatedinthenon-
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 expressedinthemedialrostralhypothalamus,aswellasthefrontal
these separately. and temporal regions of the human brain [92]. In vitro assays
Genomic imprinting (the process by which genetic effects are suggestthatSRYcanincreasetranscriptionoftyrosinehydroxylase
influenced by whether the genes are transmitted through the (therate-limitingenzymeindopaminebiosynthesis)bybindingat
fatherorthemother[81])isalsoofinterest.Ordinarilythiswould a promoter site [93]. In addition, the knockdown of SRY
notresultinsexdifferencesintherateofacondition,butcoulddo expression in the substantia nigra of the rat decreases tyrosine
so if the imprinting affects the X chromosome. Skuse [82,83] hydroxylaseexpression[94].ThiscouldimplicateSRYinthemale
suggestedthatanimprintedX-locuscouldexplainsexdifferences bias for disorders involving disregulated catecholamines such as
in social and communication skills and the male vulnerability to ADHD.SRYmayalsoregulatethemonoamineoxidaseA(MAO-
socialandcommunicationimpairment.Histheorywasinspiredby A) gene [95]. Other Y-linked genes known to be expressed in
thefindingthatinindividualswithTS,therateofsocialdifficulties human brain includeZFY andPCDH11Y[92,96].
varied according to whether their single X chromosome was Asmallcandidategenestudyfailedtofindassociationsbetween
inheritedfromthefather(X Ocases) orthemother(X O cases) variants in PCDH11Y and autism [96], while ZFY has not been
p m
(where ispaternal,and ismaternal)[82].Socialproblemsare specificallyinvestigated.Onestudyhasreportedamissensevariant
p m
greater in X O relative to X O individuals. Typical females in NLGN4Y in a single patient with autism and his father with
m p
always inherit an X chromosome from both parents (X X ), but learningdifficulties[97].ComparisonofYchromosomehaplotype
p m
typical males always have only a maternal X (X Y). Skuse groups between cases and controls represents an alternative
m
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 havebeenconductedinregardtoASC—onewaspositive[98]and
extrapolation, asa protective factor againstASC. one was negative [99]. Y chromosome effects certainly merit
Creswellandcolleagues[84]subsequentlyreportedfivecasesof additionalresearchattention,butcurrentevidenceistoosparseto
ASC from an unselected sample of 150 subjects with TS. All the evaluatetowhatextentthismechanismcouldexplainthesexbias
cases wereX O(orhadastructurally abnormal paternalX).All inASC.
m
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 Forcompletenesswebrieflymentionafinaltheory,arisingfrom
difficulties(i.e.,applicableonlytoclassicautismratherthanthefull studies of rare CNVs with ASC [67,74,100,101]. As mentioned
autisticspectrum,whichincludesAS).Also,giventhat77%ofTS earlier, these scans have not routinely implicated the X
femalesareX O,whileonly23%areX O[85],thismeansthat chromosome, but this final model proposes that a significant
m p
bychanceonewouldexpecttofindASCmoreoftenassociatedwith proportion of ASC cases are the result of dominant de novo
X Othan with X O. mutations (on the autosomes) which have reduced penetrance in
m p
No specific X-linked genes have yet been identified which females. Statistical analysis of ASC family data has provided
explainthesefindings,butthereisevidencethatwhichevergenes supportingevidence[102].Aproblemforthistheory,however,is
areinvolvedmaymodulateamygdalacircuitswhicharedisrupted that the majority of studies report that the sex ratio in children
inASC[86].Whilsttheamygdalahasnotbeendirectlyexamined, withASCanddenovoCNVsis1:1.Thisclearlydoesnotfitwith
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Table5.RatesofASC/autistictraitsindifferentmedicalconditions,aspredictedbytheXandYchromosometheories,andthefT
theory.
PredictionfromX-Dosageor Predictionfrom PredictionfromY- PredictionfromFT
MedicalCondition X-LinkedRecessiveModel ImprintedXModel ChromosomeModel Theory
CompleteAndrogenInsensitivity Similartotypicalmales Similartotypicalmales Similartotypicalmales Similartotypicalfemales
Syndrome(CAIS)inmales
CongenitalAdrenalHyperplasia Similartotypicalfemales Similartotypicalfemales Similartotypicalfemales Similartotypicalmales
(CAH)infemales
TurnerSyndrome(witha Similartotypicalmales Similartotypicalmales Similartotypicalfemales Similartotypicalfemales
maternalX;XmO)
TurnerSyndrome(witha Similartotypicalmales Similartotypicalfemales Similartotypicalfemales Similartotypicalfemales
paternalX;XpO)
doi:10.1371/journal.pbio.1001081.t005
reduced penetrance in females [103]. A second problem for this moreresearchbecausepresentingthemasindependentignoresthe
theoryisthatitdoesnotaddresswhypenetranceshouldbereduced factthatbotharerelatedtofT.NorcanweyetextrapolatethefT
in females. However, we agree that it is critical that large-scale resultstoindividualswithanASCdiagnosissincethiswillrequire
linkage and associationstudiestest for sex-specific effects. muchlargercollectionsofamnioticsamplesthanhasbeenpossible
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 eitherdiagnosed AS and/orautistic traits.
potentialexplanationsforthebiasedsexratioinASCandwarrant
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.
mayberegulatedbyfTorhaveproductsthataffecttheproduction ADHD: fT has been implicated by several studies using
orsensitivityofanindividualtofT.Xchromosomegenesmayalso 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
early androgen exposure affects catecholamine innerva-
independent riskfactors forASC.
tion of the frontal cortex and cognitive function [187].
The theories do, however, make contrasting predictions for
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
thepresenceofatypicalmalegeneticcomplement(XY).Giventhe
[191]. However, genome-wide scans have not implicated
rarity of this condition, studies using measures of autistic traits
the Xchromosome 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 haveshown relationshipswith CD [194–196], but
predictions are summarized inTable5.) there is not a simple one-to-one correspondence. In
Finally,whilstitmaybethatthepsychiatricclassificationsystem addition,theX-linkedgenecodingformonoamineoxidase
is‘‘carvingnatureatitsjoints,’’itisalsopossiblethatsomeofthe 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 ReadingDisorder/Dyslexia:Twostudieshavefailedto
neurodevelopmental conditions (seeBox 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-
proposedtheextrememalebraintheory,thispotentialcluetothe tween amniotic fT levels and early vocabulary [46,200]
could indicate a role for fT in SLI. Genome-wide linkage
etiologyoftheconditionwentunexplored[105].Intheearlyyears
studieshavenotimplicatedtheXchromosome[201–203].
following the publication of the EMB theory, the majority of the
TouretteSyndrome:TicsinindividualswithTSincrease
evidence relevant to the theory came from psychological studies,
in intensity during puberty, suggesting an activational
but since 2001supportingevidence hasalso comefrombiology.
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,
thatfetaltestosteroneisinvolvedinsexdifferencesinkeyareasof
andspatialskillsinindividualswithTS[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.
ingtherelationshipbetweenempathyandsystemizingwillrequire
PLoSBiology | www.plosbiology.org 6 June2011 | Volume 9 | Issue 6 | e1001081
The main alternatives to the fT theory are the X and Y relatingprenatalhormonestomasculinizationofthemindandthe
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 TextS1 Supplementary material.
betweenASCandmalenesshasgeneratedanovelframeworkfor (DOC)
exploring the link between sex and ASC, and a wealth of data
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