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Collaboration on the Genetics of Autism; Success and Failure

Collaboration on the Genetics of Autism; Success and Failure. Dr Peter Szatmari Offord Centre for Child Studies. Objectives. Review evidence for involvement of genetic factors in autism What are latest results? What are the obstacles? What is the way forward?

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Collaboration on the Genetics of Autism; Success and Failure

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  1. Collaboration on the Genetics of Autism; Success and Failure Dr Peter Szatmari Offord Centre for Child Studies

  2. Objectives • Review evidence for involvement of genetic factors in autism • What are latest results? • What are the obstacles? • What is the way forward? • Bottom line; importance of multi-disciplinary collaborations

  3. Understanding the Etiology of Autism • No story makes sense • A genetic variant may be the first cause, first piece of the puzzle • Other pieces may fall into place

  4. Potential Benefits of finding Genes in Autism • Earlier, more precise, diagnosis • Earlier diagnosis • Understanding the biochemical chain of events that lead to autism for better biomedical treatments

  5. Steps in Finding Autism Genes • Does the disorder run in families? • Is so, is that due to genetic factors? • If so, can chromosomal regions that carry susceptibility genes be identified? • If so, can the genes that cause the disorder be identified? • How do genetic variants cause autism?

  6. Does the disorder run in families? • Risk of autism to sibs; 3-5% • But stoppage rules will underestimate risk • Sibling recurrence risk 9%? • Compared to general population rates of 20 per 10,000 • Roughly 45 times population rate

  7. Twin Studies Results MZ vs DZ concordance is 60% vs 0-5% Given certain assumptions; heritability greater than 90% • Most heritable psychiatric disorder! • Does not exclude gene-environment interactions

  8. But Genetics are Complex • Mode of transmission non-Mendelian, • Low risk to sibs, • Prevalence is stable • Sex ratio; 4 boys to every girl

  9. Elements of Complexity • Many different genes independently cause ASD? • Many different genes cause different components of ASD? Symptoms, low IQ, language delay etc • Or epigenetic mechanisms? Or environmental interactions?

  10. In what chromosomal region? • But strong genetic effects so linkage studies can be used • Based on transmission together of genetic marker (location known) and disease genes (location unknown) • Developed for classic genetic disorders; ie CF, TS etc

  11. Genome Scan with Affected Sib Pairs • Do not have pedigrees, only affected sib pairs • Saturate the genome with 400 markers, 10 cM, apart across all chromosomes • >100 sib pairs • Significant regions; lod scores >3.0 • Suggestive regions; lod scores>1.5

  12. Regions of Interest in Autism • 9 separate genome scans completed • Between 17 and 350 sib pairs • No significant linkage detected! • Multiple “suggestive regions” identified • Have we hit the wall? • Could not get beyond step #3.

  13. Limitations of Genome Scans • Developed for pedigrees not ASP’s • Very sensitive to genetic heterogeneity • Been studying the wrong phenotype? • Many genes of small effect? • So…need a very large sample size

  14. Autism Genetics Project • 13 different research groups • -170 scientists in 57 academic centres and institutions in 19 countries • -Worldwide commitment from scientists and funding agencies • -Memorandum of Understanding between all scientists of a process of working together

  15. AGP Genome Scan • 10K SNP chip and 400 STRP’s, many more markers • Alternative phenotype definitions • Look at specific sub groups • Teams of phenotype experts, statistical geneticists, and molecular biologists • Everybody wants to be on Team Canada!

  16. Autism Genome Project: -9 Canadian co-PIs, 5 collaborators in 7 cities -170 scientists in 57 academic centres and institutions in 19 countries -Worldwide commitment from scientists and funding agencies -Memorandum of Understanding between all scientists -Canadian AGP -Canadian + international AGP

  17. AGP; current status • 1600 ASP’s • DNA sent for genotyping • Identify sub-groups and better phenotypes • Results soon available • One of the largest collaborations of any human disease!

  18. Next Steps? • NIH, CIHR and others put forward a RFA for identification of genes in “significant regions” • AGP put in a proposal • Low ranking; “not innovative”, and not funded • What now?

  19. Lessons learned • International collaboration very exciting, informative and educational • For Canadians, many new opportunities • Importance of MOU, based on trust and respect, rules of collaboration set out • A consensus approach to science carries its own risk! But still worth it!

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