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Autism: Connecting Genes to Brain to Cognition

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. Environment. Gross Anatomy. Microscopic. Cerebral Structure. Chemical. Molecular.

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Autism: Connecting Genes to Brain to Cognition

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  1. 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

  2. Development Genes Environment Gross Anatomy Microscopic Cerebral Structure Chemical Molecular Cognitive Function

  3. Rare Variation (mutation) • Common Variation • Syndrome of ASD • Endophenotypes Clinical Investigation Autism Genes Basic Investigation Laterality or Human Brain Patterning (circuit development). Evolutionary/ Cross Species Comparison (Human Cognitive Specializations)

  4. 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. What is Autism?

  5. 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

  6. 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

  7. Create a Large, Open Resource Autism GeneticResource 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

  8. 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

  9. 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 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

  10. AGP Linkage analysis # multiplex N = 522 N = 731 11p12-13 N = 1168 Nature Genetics 2007

  11. 1q21: three families Previously implicated in MR AGP Copy Number Variants 17p12: three families SM, CMT 2p16: 2 affected siblings NRX1 17 22q11.2: two families Interpretation complicated 22 • 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 1 2

  12. DeNovo CNV found in: • 3% familial cases and • 10% of simplex cases • 1% controls (all dups)

  13. The Autisms Geschwind and Levitt, 2007

  14. OCD AUTISM Social Behavior Rare disorders 10% Language epilepsy in 30% “Endophenotypes” Coexistence with other neurodevelopmental disorders

  15. 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?

  16. Language delay Stratification By Sex Solutions to complex genetics: endophenotypes .

  17. 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). (Parent-teacher correlation =.76) *Constantino et al., 2000, 2004

  18. 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

  19. 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).

  20. (Microarray Analysis of ASD with known genetic causes) Geschwind 2001 Nature Reviews Neuroscience Vol 2 (6): 437 Macmillan Magazines Ltd

  21. Gene Expression also overlaps significantly Gene Expression can distinguish ASD subjects by etiology Nishimura et al. in press (dup)15, FMR1, Control

  22. Common Variant High Density SNP analysis Replication Rare Variant Re-sequence candidate genes, Cytogenetic abnormalities Causal Disease Variant Identification of Autism Susceptibility Genes • Find Chromosomal Region by linkage analysis. • Search through genic regions to find gene (s) using association analysis.

  23. Chr 7 Association with Age at First Word (2758 SNPs)

  24. 390K 85K CNTNAP2 deletion in AU383 1.0 • 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. 0.9 Probe Ratio 0.8 0.7 0.6 0.5 Not deleted Deleted Unknown (all homozygous) SNP Genotyping 145500 145600 145700 145800 145900 146000 Chromosome 7 Location (kb)

  25. CASPR2 is enriched in human fetal frontal cortex and basal ganglia Its expression appears to mark a cortical-striatal-thalamo (and limbic) circuitry known to be involved in response selection and inhibition and language learning, Brett Abrahams, PhD

  26. 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.

  27. 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

  28. 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?”

  29. Acknowledgements 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 • 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) AGRE Clara Lonjonchere PhD Nancy Hart webmaster Cure Autism Now Foundation

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