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

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Presentation on theme: "Copy Number Variants in Autism …what are we missing? Lauren A. Weiss Dept. Psychiatry Institute for Human Genetics Center for Neurobiology and Psychiatry."— Presentation transcript:

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 disease genesQTsenvironment

8 Complex Genetics Common polymorphism Rare variant

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

10 Genome-Wide Association Common polymorphism Usually case-control –TDT for family-based association TU A50 B05 casecontrol A B

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 BroadAffy 5.0AGRE850 mpx JHU Affy 5.0/500K NIMH240 mpx CHOP (linkage only) Illumina HH550 AGRE120 mpx Many! (replication only) Affy 5.0/500K, Sequenom Varied2400 trios Site Platform Source N families

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

15 Linkage Results NPL LOD Score ,150 high quality markers in 878 multiplex families

16 Top Linkage Chr6 Chr15 Chr17 Chr20 Chr6 Chr15 Chr17 Chr20

17 SNP Association Results X log 10 P chr

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

19 Top Association Chr5, kb SEMA5A TAS2R1

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

21 SEMA5A Brain Expression Fold Expression P = Control Autism

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 Copy Number Analysis Physical position (kb) Chr 15 Duplications Individual mom dad autism

24 16p11.2 microdeletion/duplication SPN QPRT c16orf54 MAZ PRRT2 MVP CDIPT c16orf53 KIF22 SEZ6L2 ASPHD1 KCTD13 LOC TAOK2 HIRIP3 CCDC95 DOC2A FAM57B ALDOA PPP4C TBX6 YPEL3 GDPD3 MAPK3 CORO1A BOLA2 GIYD1/2 SULT1A3/4 BOLA2 GIYD1/2 SULT1A3/ p11.2

25 16p11.2 microdeletion/duplication SampleDeletionDuplication freq case vs freq control P-value del+dup AGRE 751 multiplex autism families 2814 controls 5 cases 3 controls 7 cases 0 controls 0.8% vs 0.1% 1.1 x 10 -4

26 16p11.2 microdeletion/duplication SampleDeletionDuplication freq case vs freq control P-value del+dup Children’s Hospital 512 DD/MR/ASD 434 congenital anomalies (not including DD/MR/ASD) 5* cases 0 controls 4 cases 0 controls 1.6% vs x 10 -3

27 16p11.2 microdeletion/duplication SampleDeletionDuplication freq case vs freq control P-value del+dup deCODE 299 ASD cases 18,834 unscreened controls 5,019 psych/lang disorders 3 cases 2 controls 5 psych/ lang 0 cases 5 controls 1% vs. 0.01% 4.2 x (0.1% in psych/lang)

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 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 Novel CNVs associated with autism

30 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 Novel CNVs associated with autism

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

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

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

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

43


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