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Copy Number Variants in Autism …what are we missing?

Copy Number Variants in Autism …what are we missing?. Lauren A. Weiss Dept. Psychiatry Institute for Human Genetics Center for Neurobiology and Psychiatry. Autism. Specific impairment in: Language and communication Social skills Restricted and repetitive behavior

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Copy Number Variants in Autism …what are we missing?

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  1. Copy Number Variants in Autism …what are we missing? Lauren A. Weiss Dept. Psychiatry Institute for Human Genetics Center for Neurobiology and Psychiatry

  2. Autism • Specific impairment in: • Language and communication • Social skills • Restricted and repetitive behavior • Clinically very heterogeneous • MR, epilepsy, hyperserotonemia, GI problems, regression, savant skills, sensory hypersensitivity, head growth

  3. What we know • A Pervasive Developmental Disorder • Prevalence of ASDs ~0.6% • 4:1 male to female ratio • Estimates of >90% heritability • Siblings at increased risk • Large role for inherited genetics vs. sporadic events and environmental factors • no genes identified in majority

  4. Known Genetic Causes of Autism • Chromosomal/Structural variants associated with autism • Rare mutations associated with autism • Account for ~10%

  5. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS) • 7q11.23 (Williams Syndrome) • 22q11.2 (diGeorge/VCFS) • 22q13 (Phelan-McDermid syndrome) • 17p11.2 (Smith-Magenis/Potocki-Lupski)

  6. Single Base Mutations in Autism • NLGN3, NLGN4X • MECP2 (Rett Syndrome) • TSC1/2 (Tuberous Sclerosis) • PTEN (Cowden Disease) • SHANK3 • CACNA1C (Timothy Syndrome) • DCHR7 (Smith-Lemli-Opitz Syndrome)

  7. Complex Genetics genes QTs environment disease

  8. Complex Genetics Common polymorphism Rare variant

  9. Study Design >1000 multiplex families CNV analysis Linkage analysis SNP/CNV association Validation and Typing of CNVs Identification Of risk genes In linkage/CNV regions Replication studies Follow up of autism risk factors

  10. Genome-Wide Association • Common polymorphism • Usually case-control • TDT for family-based association

  11. Genome-Wide Association • Common polymorphism • Usually case-control • TDT for family-based association • LARGE sample size required • 1,000s to 10,000s • MANY markers across the genome • 500,000 to 1,000,000

  12. Copy Number Variation • Greater than 1 kb in/del • Normal copy number 2 • Rare, common? • Detection methods • Karyotype, CGH, FISH, MLPA, qPCR • SNP arrays • Whole genome, small events, boundary estimates

  13. Datasets Site N families Source Platform

  14. Analysis Methods • Genotype calling by Birdseed • Careful QC pipeline • Linkage analysis in MERLIN • Association analysis by TDT in PLINK

  15. Linkage Results • 16,150 high quality markers in 878 multiplex families 3 2 1 NPL LOD Score 0

  16. Top Linkage Chr15 Chr6 Chr15 Chr6 Chr20 Chr17 Chr20 Chr17

  17. SNP Association Results 6 5 4 3 2 1 -log10P 1234567891011121314151618 20 22 chr 17 1921X

  18. Replication • Top results (P < 10-4) into replication • Additional Affy microarray data • Sequenom genotyping (TaqMan) • extra cases vs. controls • rs10513025 on 5p15 replicates P < 0.006 • MAF 0.04, OR 0.5 • Combined P = 2 x 10-7

  19. Top Association TAS2R1 SEMA5A Chr5, kb

  20. Top Association rs10513025 meta-P = 2 x 10-7 TAS2R1 SEMA5A Chr5, kb

  21. SEMA5A Brain Expression Fold Expression Control Autism P = 0.039

  22. SNP Results Summary • Genome-wide significant linkage on 20p • Association on 5p15 near SEMA5A • Replicated independently • Very low/high frequency variation implicated • More to find!

  23. Chr 15 Duplications 0 1 2 3 4 5 0 1 2 3 4 5 mom autism Individual 0 1 2 3 4 5 0 1 2 3 4 5 dad autism Physical position (kb) Copy Number Analysis

  24. 16p11.2 microdeletion/duplication 16p11.2 29 29.5 30 30.5 31 29.5 29.9 30.0 30.1 29.6 29.7 29.8 ASPHD1 MVP MAPK3 BOLA2 c16orf54 SPN CORO1A LOC124446 TBX6 FAM57B KIF22 QPRT GIYD1/2 CDIPT KCTD13 TAOK2 BOLA2 ALDOA YPEL3 SEZ6L2 MAZ SULT1A3/4 HIRIP3 PPP4C GDPD3 GIYD1/2 PRRT2 CCDC95 SULT1A3/4 DOC2A c16orf53

  25. 16p11.2 microdeletion/duplication

  26. 16p11.2 microdeletion/duplication

  27. 16p11.2 microdeletion/duplication

  28. Copy Number Summary • 16p11.2 microdeletion/duplication found in 1-2% of autism cases, <0.1% controls • Three independent samples • Large Icelandic population sample • 0.1% in psych/lang disorder, 0.01% population • 15q11-q13 duplications, including partial • Follow-up and additional controls required for more common and inherited events

  29. Novel CNVs associated with autism • 16p11.2 • Deletion, high penetrance, variable expression • Duplication, reduced penetrance, variable expression • 15q13.3 • Deletion, high penetrance, variable expression • Duplication, reduced penetrance, variable expression • 1q21.1 • Deletion, high penetrance, variable expression • Duplication, reduced penetrance, variable expression

  30. Novel CNVs associated with autism • 16p11.2 • Autism, PDD/Asperger’s, ADHD, MR/DD, epilepsy, schizophrenia, bipolar disorder, dyslexia • 15q13.3 • Epilepsy, MR/DD, schizophrenia, autism, language delay, dysmorphism • 1q21.1 • Micro/macrocephaly, MR/LD, autism, ADHD, schizophrenia, epilepsy, dysmorphism, congenital anomalies, short stature

  31. Structural Variants in Autism • X chromosome (Turner, Klinefelter)

  32. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X)

  33. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS)

  34. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS) • 7q11.23 (Williams Syndrome)

  35. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS) • 7q11.23 (Williams Syndrome) • 22q11.2 (diGeorge/VCFS)

  36. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS) • 7q11.23 (Williams Syndrome) • 22q11.2 (diGeorge/VCFS) • 22q13 (Phelan-McDermid syndrome)

  37. Structural Variants in Autism • X chromosome (Turner, Klinefelter) • FMR1 (Fragile X) • 15q11-q13 duplication (PWS/AS) • 7q11.23 (Williams Syndrome) • 22q11.2 (diGeorge/VCFS) • 22q13 (Phelan-McDermid syndrome) • 17p11.2 (Smith-Magenis/Potocki-Lupski)

  38. Implications for CNV studies • Reverse genetic screen • Common, small CNV associations?

  39. Single Base Mutations in Autism • NLGN3, NLGN4X • MECP2 (Rett Syndrome) • TSC1/2 (Tuberous Sclerosis) • PTEN (Cowden Disease) • SHANK3 • CACNA1C (Timothy Syndrome) • DCHR7 (Smith-Lemli-Opitz Syndrome)

  40. Implications for SNP studies • Are narrow phenotype definitions useful? • Population re-sequencing? • Genetic overlap (e.g. autoimmune syndromes) • Meta-analysis? Guillaume Lettre and John D. Rioux Human Molecular Genetics, 2008, Vol. 17, Review Issue 2

  41. Implications for Neurobiology • Underlying QT • E.g. Diabetic retinopathy, neuropathy, periodontal disease, nephropathy, cardiovascular disease, reproductive disorders • Heritable modifiers?

  42. Acknowledgements • Mark Daly • Pamela Sklar • Aravinda Chakravarti • Dan Arking • AGP, CHOP, and replication groups

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