Post on 20-Jan-2016
Autism: Connecting Genes to Brain to Cognition
Daniel H Geschwind, MD PhDDaniel H Geschwind, MD PhD
Departments of Neurology, Psychiatry and Departments of Neurology, Psychiatry and Human GeneticsHuman Genetics
UCLA School of MedicineUCLA School of Medicine
HUGO May 2007
Cognitive Function
Cerebral Structure
Gross Anatomy
Microscopic
MolecularChemical
DevelopmeDevelopmentnt
Genes Environment
Autism Genes
Rare Variation(mutation)
Laterality or Human BrainPatterning (circuit development).
Common Variation •Syndrome of ASD•Endophenotypes
Evolutionary/Cross Species Comparison (HumanCognitive Specializations)
Clinical Investigation
Basic Investigation
What is Autism?
• Autism is a neuropsychiatric syndrome first described in 1943.
• characterized by deficits in 3 domains:– Communication/
Language– Social interactions– Restrictive, repetitive
behavior
• Onset prior to 3 years of age.
• 4:1 ratio of male to female
• 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 Autismis 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 15-30% of children with FRAX have autistic features)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 GeneticAutism GeneticResource ExchangeResource Exchange
• An open resource shared An open resource shared with the scientific with the scientific communitycommunity
• More than 750 families.More than 750 families.
• 10k SNP Genome Scan and 10k SNP Genome Scan and fine mapping datafine mapping data
• Phenotype data: Phenotype data: – ADI-R, ADOSADI-R, ADOS
– basic cognitive and language basic cognitive and language testingtesting
– physical/neuro examsphysical/neuro exams
– medical historiesmedical histories
• Karyotyping/molecular cytogenetics
Autism Full Genome Scans 1998 - 2003
IMGSAC (1998) 99 familiesIMGSAC (1998) 99 families
CLSA, Barrette et al. (1999) 75 familiesCLSA, Barrette et al. (1999) 75 families
Risch et al. (1999) 139 familiesRisch et al. (1999) 139 families
Phillipe et al. (1999) 51 familiesPhillipe et al. (1999) 51 families
IMGSAC (2001) 152 familiesIMGSAC (2001) 152 families
AGRE, Liu et al. (2001) 110 familiesAGRE, Liu et al. (2001) 110 families
Shao et al. (2002) 90 familiesShao et al. (2002) 90 families
Auronen et al. (2002) 38 familiesAuronen et al. (2002) 38 families
AGRE Yonan et al. (2003) 345 familiesAGRE Yonan et al. (2003) 345 families
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 Lese-Martin); 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
Autism Genome Project (AGP)Autism Genome Project (AGP)
AGP Linkage analysis
N = 522
N = 731
N = 1168
# multiplex
11p12-13
Nature Genetics 2007
AGP Copy Number Variants
1 2
2p16: 2 affected siblingsNRX1
1q21: three familiesPreviously implicated in MR
17
17p12: three families SM, CMT
22
22q11.2: two familiesInterpretation complicated
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)
Geschwind and Levitt, 2007
The Autisms
Coexistence with other neurodevelopmental
disorders
AUTISM
epilepsy in 30%
Rare disorders
10%
Language
OCD
Social Behavior
“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
StratificationBy Sex
Language delay
Endophenotype: Social Behavior (Social Responsiveness
Scale*)
SRS SCORE
Non Autistic Sibs of Autistic Probands _ AGRE25
20
15
10
5
0
Std. Dev = 39.47
Mean = 56.8
N = 61.00
SRS SCORE
180.0170.0
160.0150.0
140.0130.0
120.0110.0
100.090.0
80.070.0
60.050.0
40.030.0
20.010.0
0.0
Clinical Control Sibs _ WASH U 25
20
15
10
5
0
Std. Dev = 27.92
Mean = 28.9
N = 46.00
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).
(Parent-teacher correlation =.76) *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).
Geschwind 2001 Nature Reviews NeuroscienceVol 2 (6): 437 Macmillan Magazines Ltd
(Microarray Analysis of ASD
with known genetic causes)
Gene Expression can distinguish ASD subjects by etiology
(dup)15, FMR1, Control
Gene Expression also overlaps significantly
Nishimura et al. in press
Identification of Autism Susceptibility Genes
• Find Chromosomal Region by linkage analysis.• Search through genic regions to find gene (s)
using association analysis.
Common VariantHigh Density SNP analysis Replication
Rare VariantRe-sequence candidate genes,Cytogenetic abnormalities Causal Disease Variant
Chr 7 Association with Age at First Word (2758 SNPs)
Basepair Position
P
eulav
0.1
0.01
0.001
138Mb 140Mb 142Mb 144Mb 146Mb 148Mb 150Mb 152Mb
CNTNAP2
KIAA1549
PRKAG2TIF1
ATP6V0A4OR9N1P ZNF398
FLJ42291
145500000.000145600000.000
145700000.000145800000.000
145900000.000146000000.000
CHROM.POS
100.0
5
6
7
8
9
383-3 85K (JT877)383-3 390K (JT2425)
Not deletedDeletedUnknown (all homozygous)
SNP Genotyping
390K
85K
145500 145600 145700 146000145800 145900
Chromosome 7 Location (kb)
0.7
0.5
0.6
0.8
1.0
0.9
Pro
be
Ra
tio
CNTNAP2 deletion in AU383
•21 SNPs exhibited the same non-Mendelian pattern of inheritance, ranging from 145,663,096 – 146,826,809 base pairs, within the CNTNP gene in autistic individual.
CASPR2 is enriched in human fetal
frontal cortex and basal ganglia
Brett Abrahams, PhD
Its expression appears to mark a cortical-striatal-thalamo (and limbic) circuitry known to be involved in response selection and inhibition and language 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?”
AcknowledgementsUniversity of Chicago (microsatellite genotyping)Conrad GilliamJJ LiuAmanda Yonan
Emory University (cytogenetics)Christa Leese-MartinDavid Ledbetter
CSHLJonathan SebatMike Wigler
Mattew StatePat Levitt
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
AGRE Clara Lonjonchere PhDNancy Hart webmasterCure Autism Now Foundation
Funding Sources: NIMH (R01 and STAART;
DHG)CAN (DHG), Autism SpeaksM.I.N.D. Institute (MA, SS)