1. Brett S. Abrahams, PhD brett.abrahams@gmail.com Risk prediction in the autisms

2. The autisms encompass a diverse range of behavioral disorders Core Impairments: - Language Use - Social Behavior - Behavioral Flexibility Asperger Pervasive Developmental Disorder NOS Autistic Disorder Rett Syndrome Childhood Disintegrative Disorder

3. The number of implicated regions is large and growing Abrahams and Geschwind, Nature Reviews Genetics, 2008 25-100x increased risk for the sibling of an affected child

4. Important insights and opportunities from new technologies Abrahams and Geschwind, Nature Reviews Genetics, 2008 Linkage PeaksCommon VariantsRare Syndromes Abrahams and Geschwind, from Vogel and Motulsky’s Human Genetics, 2009

5. Autism in most cases likely the result of multiple independent risk factors

6. Observations made in one cohort often fail to be observed in others Veronica Vieland, Nationwide Children’s Hospital Genetic heterogeneity makes replication difficult

7. Risk Prediction for Siblings of Children With Autism Spectrum Disorder A Combination of Four Genes G Dawson, GD Schellenberg, A Ziegler, IR König, F Rousseau J Carayol, O Korvatska, J Munson, A Estes, C-E Yu, J Hager Sponsored by IntegraGen, SA

8. Staged design employed to test reproducibility Discovery Cohort (AGRE) 276 multiplex families genotyped at four positions “risk scores” compared between cases and pseudo- controls Replication Cohort (Univ. Washington) 295 multiplex families genotyped at as above Genetic scores compared between cases and controls

9. Risk score (RS) Sum number of risk alleles over 4 SNPs Specificity Proportion of individuals without the disease correctly identified by the test Sensitivity Proportion of individuals with the disease correctly identified by the test Sensitivity and specificity InboxSpam Folder EmailCorrectly Classified Incorrectly Classified SpamIncorrectly Classified Correctly Classified

10. The risk score (RS) is a measure of genetic similarity to other cases Genotype Population Frequency

11. Individual variants inconsistently associated with disease status Odds ratios for individual variants each less than two

12. Higher risk score reproducibly elevated in cases versus controls

13. Highest risk scores associated with increased likelihood of disease

14. Conclusions Looking forward - Autism genetics are complex but much has and is being learned - High risk scores are associated with a 2-3x increased risk for autism, an effect much larger than that for individual common variants - Estimates for increased risk (2-3x), specificity (~93%), and sensitivity (~21%) are consistent between populations - Current and future tests may prove helpful in risk assessment in children with a sibling with autism - Ongoing work will improve risk assessment further - Increased sensitivity critical (RS < 7 not currently informative) - Back and forth between laboratory and clinic is essential

15. Investigators Gerard Schellenberg, PhD –University of Washington and VA Seattle, WA Olena Korvatska, PhD and Chang-En Yu –VA Seatlle, WA Jeff Munson, PhD and Annette Estes, PhD –University of Washington Autism Center, Seattle, WA Andreas Ziegler, PhD and Inke R. König, PhD –Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Germany –StatSol, Sereetz, Germany IntegraGen Employees Jérome Carayol, PhD Jörg Hager, PhD Mélanie Letexier Frédéric Tores, B.Sc. Francis Rousseau, PhD Acknowledgements