Transcript Autism - HGM2007

Autism: Connecting Genes to
Brain to Cognition
Daniel H Geschwind, MD PhD
Departments of Neurology, Psychiatry and Human
Genetics
UCLA School of Medicine
HUGO
May 2007
Development
Genes
Gross Anatomy
Microscopic
Chemical
Molecular
Environment
Cerebral
Structure
Cognitive Function
Rare Variation
(mutation)
Common Variation
•Syndrome of ASD
•Endophenotypes
Autism Genes
Clinical Investigation
Basic Investigation
Laterality or Human Brain
Patterning (circuit
development).
Evolutionary/
Cross Species Comparison (Human
Cognitive Specializations)
What is Autism?
• Autism is a
neuropsychiatric
syndrome first described
1943.
• 4:1 ratio of male to female
in
• characterized by
deficits in 3 domains:
– Communication/Language
– Social interactions
– Restrictive, repetitive
behavior
• Onset prior to 3 years
of age.
• Effects 1 in 200 children
today.
• More common than other
childhood disorders, ie
childhood cancer, DM,
Down’s
• Normal life expectancy.
•
10-25 % will develop
epilepsy
• Autistic behaviors shared
by many other disorders,
ie: TS, Fragile X, untreated
PKU and others.
Idiopathic Autism
is the most heritable of
neuropsychiatric syndromes
• Sibling recurrence risk is 6-10%
• This translates to a 25-65 fold increase
over the general population risk (depending on
what incidence rate you use).
• Twin studies:
– MZ 60-70% concordance for strict autism
– 90% for autism spectrum
– Published DZ concordance 0-6%
– Heritability = 0.7 to 0.9
Autisms - Known Genetic Causes
About 10% of individuals with ASD have
identifiable genetic disorders:
• Chromosome abnormalities: ~5-10% (1-2% (dup)15q)
• Fragile X syndrome: 1-2% (15-30% of children with FRAX
have autistic features)
• Rett syndrome: <1%
• Tuberous Sclerosis: <1%
• Angelman syndrome: when dx’d with AS, ~50% have
autism
• Very Rare mutations
Create a Large, Open Resource
Autism Genetic
Resource Exchange
• An open resource shared
with the scientific
community
• More than 750 families.
• 10k SNP Genome Scan
and fine mapping data
• Phenotype data:
–
–
–
–
ADI-R, ADOS
basic cognitive and language
testing
physical/neuro exams
medical histories
• Karyotyping/molecular
cytogenetics
Autism Full Genome Scans
1998 - 2003
IMGSAC (1998) 99 families
CLSA, Barrette et al. (1999) 75 families
Risch et al. (1999) 139 families
Phillipe et al. (1999) 51 families
IMGSAC (2001) 152 families
AGRE, Liu et al. (2001) 110 families
Shao et al. (2002) 90 families
Auronen et al. (2002) 38 families
AGRE Yonan et al. (2003) 345 families
Autism Genome Project (AGP)
Autism Genetics Collaborative (AGC)
Duke (Margaret Pericak-Vance, Michael Cuccaro, John Gilbert); Mt. Sinai School of Medicine
(Joseph Buxbaum, Jeremy Silverman, Christopher Smith); Paris Autism Research
International Sibpair Study (Catalina Betancur, Thomas Bourgeron, Marion Leboyer);
Stanford University (Joachim Hallmayer); University of Iowa (Veronica Vieland, Thomas
Wassink); University of North Carolina (Joseph Piven); University of Toronto/Hospital for
Sick Children - McMaster University (Steve Scherer, Peter Szatmari, Andrew Paterson);
Vanderbilt University (James Sutcliffe, Jonathan Haines)
Autism Genetics Resource Exchange (AGRE)
University of California - Los Angeles (Dan Geschwind, Stan Nelson, Rita Cantor, Maricela
Alarcon, Kenneth Lange, Sarah Spence); Emory University (David Ledbetter, Christa LeseMartin); University of Chicago (Conrad Gilliam)
Collaborative Programs of Excellence in Autism (CPEA)
University of Washington (Gerard Schellenberg, Geraldine Dawson, Ellen Wijsman);
University of Utah (William McMahon, Hilary Coon); University of Pittsburgh (Bernie Devlin)
International Molecular Genetic Study of Autism Consortium (IMGSAC)
Oxford University (Anthony Monaco, Anthony Bailey, Janine Lamb); University of Bologna
(Elena Maestrini); Deutsches Krebsforschungszentrum, Heidelberg (Annemarie Poustka,
Sabine Klauk); University of Illinois – Chicago (Ed Cook); University of Michigan (Catherine
Lord)
Autism Speaks, CIHR, CAN, Genome Canada, HHMI, Hospital for Sick
Children Foundation, INSERM, MRC, NICHD, NIDCD, NIMH, NINDS, NLM
Family Foundation, Swedish National Medical Council, Wellcome Trust, EU
AGP Linkage analysis
# multiplex
N = 522
N = 731
11p12-13
N = 1168
Nature Genetics 2007
AGP Copy Number
Variants
17p12: three families
SM, CMT
2p16: 2 affected siblings
NRX1
17
1q21: three families
Previously implicated in MR
22q11.2: two families
Interpretation complicated
22
1
2
17 de novo CNVs (14 found in both ASP)
18 CNVs overlap ASD-related
rearrangements
Numerous overlapping/recurrent CNVs
Families with transmission of maternal 15q
gains
DeNovo CNV found
in:
• 3% familial cases and
• 10% of simplex cases
• 1% controls (all dups)
The Autisms
Geschwind and Levitt, 2007
Coexistence with other
neurodevelopmental disorders
OCD
Social Behavior
AUTISM
Rare
disorders
10%
epilepsy
in 30%
Language
“Endophenotypes”
ASD Endophenotypes
• Language Delay
(Age at speech milestones)
*
– Buxbaum et al. 2002 (chr 2) Alarcon et al. 2002; 2005 (Chrom
7q35, Chrom 3p)
• Social Cognition
(Responsiveness; Duvall et al. 2005)
– Chrom 11p (Z = 3.4), Chrom 17q (3.1), Chrom 5p (2.8)
• Non-verbal communication
(Chen et al. 2005)
– Chrom 16p (OSA-Lod 3.8), Chrom 8q (OSA-Lod 3.4)
• Sex (Male vs. Female)* (Stone et al. 2004; Cantor et al. 2005)
• Head Circumference*
• Seizures/Regression
• NeuroImaging or Electrophysiology
• Gene Expression?
Solutions to complex genetics: endophenotypes
.
Language delay
Stratification
By Sex
Endophenotype: Social Behavior
(Social Responsiveness Scale*)
The SRS is an established quantitative measure of autistic
social impairment which generates a singular severity score for
autistic social impairment (higher score equates with greater
severity).
Non Autistic Sibs of Autistic Probands _ AGRE
Clinical Control Sibs _ WASH U
25
25
20
20
15
15
10
10
5
5
Std. Dev = 27.92
Std. Dev = 39.47
Mean = 28.9
Mean = 56.8
0
0.
18 .0
0
17 .0
0
16 .0
0
15 .0
0
14 .0
0
13 .0
0
12 .0
0
11 .0
0
10
.0
90
.0
80
.0
70
.0
60
.0
50
.0
40
.0
30
.0
20
.0
10
0
0.
SRS SCORE
(Parent-teacher correlation =.76)
N = 46.00
0
0
0.
18 .0
0
17 .0
0
16 .0
0
15 .0
0
14 .0
0
13 .0
0
12 .0
0
11 .0
0
10
.0
90
.0
80
.0
70
.0
60
.0
50
.0
40
.0
30
.0
20
.0
10
0
0.
N = 61.00
0
SRS SCORE
*Constantino et al., 2000, 2004
Social Cognition
• SRS --parent and teacher
report
• Samples
– 105 sibships (i.e. families,
¼ of AGRE sample)
– > 200 sibpairs (i.e.
combinations of sibs)
– Used all pairs of
phenotyped sibs –
unweighted
Molecular Endophenotype: Can
peripheral gene expression identify
etiological subtypes of ASD?
• 1) Can gene expression profiles be used to differentiate
autism subjects into etiological categories.
– Can we do this for subjects with “simple” causes of autism
FMR1-FM or dup/idic 15q
• 2) Are any of the shared “candidate” pathways
dysregulated in idiopathic autism ?
• 3) Mutations emphasize role of gene regulation in related
neuro-developmental disorders
– A2BP1/FOX1 deNovo deletion (Leese- Martin et al. 2007)-neuronal specific splicing factor.
– FMR1 (RNA binding/processing).
– Rett syndrome (MeCP2).
(Microarray Analysis
of ASD with known
genetic causes)
Geschwind 2001
Nature Reviews
Neuroscience
Vol 2 (6): 437
Macmillan Magazines
Ltd
Gene Expression can
distinguish ASD subjects by
etiology
Nishimura et al. in press
(dup)15, FMR1, Control
Gene Expression also
overlaps significantly
Identification of Autism
Susceptibility Genes
• Find Chromosomal Region by linkage analysis.
• Search through genic regions to find gene (s) using
association analysis.
Common Variant
High Density SNP analysis
Replication
Rare Variant
Re-sequence candidate genes,
Cytogenetic abnormalities
Causal Disease Variant
Chr 7 Association with Age at First Word (2758
SNPs)
0.001
KIAA1549
CNTNAP2
PRKAG2
TIF1
OR9N1P
ATP6V0A4
ZNF398
P value
0.01
FLJ42291
0.1
138Mb
140Mb
142Mb
144Mb
146Mb
Base pair Position
148Mb
150 Mb
152Mb
CNTNAP2 deletion in AU383
Probe Ratio
383-3 85K (JT877)
383-3 390K (JT2425)
0.0
1.0
10
100.0
0.99
9
0.88
8
0.77
7
0.66
6
0.55
Not deleted
Deleted
Unknown (all homozygous)
5
390K
383-3
85K
383-3
85K (JT877)
390K (JT242
•21 SNPs exhibited
the same nonMendelian pattern
of inheritance,
ranging from
145,663,096 –
146,826,809 base
pairs, within the
CNTNP gene in
autistic individual.
SNP Genotyping
145500
145600
145700
145800
145900
146000
145500000.000
145700000.000
145900000.000
145500000.000
145700000.000
145900000.000
145600000.000
145800000.000
146000000.000
145600000.000
145800000.000
146000
Chromosome 7 Location
(kb)
CHROM.POS
CHROM.POS
CASPR2 is enriched in human fetal frontal
cortex and basal ganglia
Its expression appears to mark a cortical-striatalthalamo (and limbic) circuitry known to be involved
in response selection and inhibition and language
Brett Abrahams, PhD
learning,
Is Autism a Developmental Disconnection
Syndrome?
• Emerging evidence for genes potentially involved
in “connectivity”
– Common variation
• GABARB3 (Multiple)
• Met (Cambell et al. 2006)
• CNTNAP2 (Alarcon et al. unpublished)
– Rare mutations
• Neuroligin 3 and 4 (Soderstrom et al. 2003)
• Shank3 (Durand et al. 2006)
• CNTNAP2 (Strauss et al. 2006)
Neurexin 1,3 Neuregulins, CNTNAP2 (dNeurexin 4) and
others are involved in neuronal migration, pathfinding
pathways and synaptogenesis.
•Deficits are related to functioning of higher order
association areas: language, social behavior, and mental
flexibility all require rapid, extensive integration of
higher order information via 2nd and 3rd order
association areas.
•Circuits developed in primates
Summary
While ASD risk is largely genetic, its etiology is multi-factorial and
very heterogeneous.
Rare genetic variants contribute to at least 10% of cases, and are
likely to explain more (20%?).
Understanding the contribution of common variation and its
interaction with rare variants is the next step.
We have had some success, but we are learning that the standard
approaches alone are relatively weak.
Other methods: Microarray, Bio-informatics, Pathway Analysis?
WE NEED TO DROP DSM related measurements and study traits
that may be related to underlying pathophysiology or biology.
Hope for a new understanding: “Developmental
Disconnection?”
Acknowledgements
UCLA
•Maricela Alarcon: Language QTL,
•Jackie Duvall/Jen Stone:
Pathway,
•Sarah Spence: Phenotyping,
•Rita Cantor Group (New QTLs)
•Stan Nelson Group (SNPs)
Jennifer Stone (Male risk factors)
Yuhei Nishimura (microarray)
Washington University
•John Constantino
•Richard Todd (SRS)
•AGP
Funding Sources:
NIMH (R01 and STAART; DHG)
CAN (DHG), Autism Speaks
M.I.N.D. Institute (MA, SS)
University of Chicago (microsatellite
genotyping)
Conrad Gilliam
JJ Liu
Amanda Yonan
Emory University (cytogenetics)
Christa Leese-Martin
David Ledbetter
CSHL
Jonathan Sebat
Mike Wigler
Mattew State
Pat Levitt
AGRE
Clara Lonjonchere PhD
Nancy Hart webmaster
Cure Autism Now Foundation