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Why is autism more common in males?
Simon Baron-Cohen
Autism Research Centre
Cambridge University
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Cambridge-DenmarkCollaborators
Michael V Lombardo, Bonnie Auyeung,
Bhismadev Chakrabarti, Liliana Ruta,
Bent Nørgaard-Pedersen, David Hougaard, Morsi Abdallah,
Lars Melgard, Arieh Cohen
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Other Collaborators
• Psychology and Brain Scanning
Sally Wheelwright, Johnny Lawson, Nigel Goldenfeld, Jen Richler, Jen Connellan, Anna Bakti, Carrie Allison, Ed Bullmore, Howard Ring, Xavier Chitnis, Chris Ashwin, Lindsay Chura, Meng-Chuan Lai, John Suckling
• Hormones and Genetics
Gerald Hackett, Kevin Taylor, Rebecca Knickmeyer, Emma Ashwin, Svetlana Lutchmaya, Melissa Hines, Lindsey Kent, Frank Dudbridge, Erin Ingudomnukul
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Why the male bias?
•Classic autism: 4:1 •Asperger Syndrome: 9:1
•Social•Clinical factors•Genetics•Hormones (sex steroids/androgens)•An extreme of certain male-typical traits?
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Brain Volume
Lenroot & Guidd, Neuroimage, 2007,
Alonso-Nancalareset et al, 2008, PNAS
Knickmeyer et al 2008 J Neurosci
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Lenroot & Guidd, Neuroimage 2007Gilmore et al (2007) J. Neuroscience.
Grey Matter
White Matter
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Gray Matter VolumeLenroot & Guidd, Neuroimage 2007
Frontal Lobe
Temporal Lobe
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males > femalesAmygdala
Good et al. (2001) Neuroimage
females > malesPlanum Temporale(Heschl’s Gyrus)/Wernicke’s)
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Hines (2003)
Child’s play
Pierce et al (2010)
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Alexander and Hines 2002
Monkey play
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Physics, computer science, engineering, mathematics
Primary school, counseling
Occupations
Reilly 2012, Plos-One
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EmpathyIdentify another person’s thoughts and feelings
respond with an appropriate emotion
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Systemizing
Analysing or building a system
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sarcastic stern
suspicious dispirited
FemalesFemales MalesMales ASAS
22.122.1 19.5 19.5 16.616.6
(2.0)(2.0) (2.6)(2.6) (2.9)(2.9)JCPP1997
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Females > Males > Autism
Left Inferior Frontal Gyrus
fdfd
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Females > Males > Autism(EQ)
• People often tell me I went too far in driving my point home in a discussion
• I often find it difficult to judge if something is rude or polite
ASAS 20.420.4 (11.6)(11.6)
MalesMales 41.841.8 (11.2)(11.2)
FemalesFemales 47.247.2 (10.2)(10.2)
JADD 2004
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Females > Males > Autism
Corpus Planum Callosum Temporale
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Systemising Quotient
Autism > Males > Females
ASAS 35.935.9 (15.2)(15.2)
MalesMales 30.3 30.3 (11.7)(11.7)
FemalesFemales 24.124.1 (9.5)(9.5)
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ASAS ControlsControls
16.316.3 10.310.3
(3.1)(3.1) (2.8)(2.8)
Autism > Males > Females
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FemalesFemales MalesMales ASAS
66.766.7 46.246.2 32.232.2
(36.7)(36.7) (20.5)(20.5)(27.0)(27.0)
JCN, 1997
Autism > Males > Females
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Females > Males > Autism
Posterior Parietal Cortex
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BC et al, 2001
ASAS 35.835.8 6.56.5MalesMales 17.817.8 6.86.8FemalesFemales15.415.4 5.75.7
Autism > Males > Females
AQ
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Autism > Males > Females
AmygdalaSchumann et al 2010 J Neurosci
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DiffDiff MenMen WomenWomen ASAS
E > SE > S 1717 4444 11
S > ES > E 5454 1717 2727
S >> ES >> E 66 00 6565
Int. J. Clin Neuropsych (2006)
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% %
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Pierce et al 2010Arch Gen Psychiatry
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Fetal sex steroids (androgens)
• fetal testosterone (FT)
• males produce double
• organizational effects
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Cambridge Amniocentesis Study• 12-19 weeks in pregnancy (n = 619)
• 12, 24, 48, 96 months follow-up
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Feeling sorry
interested
bored
joking
Em
path
y
Fetal Testosterone
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Systemizing
Euro J Endocrin 2006
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Attention todetail
Auyeung et al, 2012
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JADD, 2001; Auyeung et al, 2009
Autistic traits
My child prefers to do things with others rather than on his/her own.
My child prefers to do things the same way over and over again.
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Corpus callosum(Chura et al 2009)
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Planum TemporaleLombardo et al 2012
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Autism and AS (n=70)
Historic Birth Cohort Denmark (n>100,000)
Singletons born 1993-99 (n=19,677)
Controls (n=219)
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progesterone
17α-hydroxy cortisol
progesterone
androstenedione
testosterone The Δ4-sex steroid pathwayCYP17-mediated (Chakrabarti et al 2009)
Cambridge-Denmark Study: ASC (n = 59) Controls (n = 219)
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HSD17B4
HSD17B2*
CYP11B1*
ESR1
ESR2
HSD11B1
LHCGR
CYP17A1
CYP19A1
SCP2
EQ /AQAS case-control
10 sex steroid genes
(* = EQ only)Chakrabarti et al, 2009 Autism Research
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Hormonal factors• Puberty (Tordjeman et al, 1997; Ingudomnukul et al, 2007)
• Polycystic Ovary Syndrome (PCOS)(Ingudomnukul et al, 2007; Kao et al, 2010)
• 2D:4D ratio(Manning et al 2001; Swettenham et al, 2006; Noipayak, 2009)
• Salivary testosterone (Schmidtova et al, 2010)
• Serum androstenedione(Ruta et al 2011)
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Conclusions / Future directions
• Fetal androgens/sex steroids play a role in sexual dimorphism in brain development and behaviour, especially autistic traits
• Fetal sex steroids interact with genetic factors and postnatal experience
• The Cambridge-Denmark study is the strong test of the fetal androgen theory of autism
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www.autismresearchcentre.com
Thanks to
The Nancy Lurie Marks FoundationMedical Research Council UK
Wellcome Trust UKTarget Autism Genome
NIHR CLAHRC
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The steroidogenic pathway