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FaceBase Kick-Off Meeting Nov 15-16, 2009 Bethesda

Explore insights from Genome-Wide Association Studies (GWAS) on oral clefts for functional genomics. The Kick-Off Meeting of FaceBase delves into genes, gene-environment interactions, and parental origin effects. Learn about the latest techniques like Next-Gen Sequencing and evaluate target capture for in-depth studies. Key genes such as IRF6, MAFB, and ABCA4 are under scrutiny. Join the journey towards understanding the genetic complexities of oral clefts.

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FaceBase Kick-Off Meeting Nov 15-16, 2009 Bethesda

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  1. FaceBase Kick-Off MeetingNov 15-16, 2009Bethesda Oral Clefts: Moving from Genome Wide Studies Toward Functional GenomicsTH Beaty for Alan F Scott, Ingo Ruczinski, Hong Kai Ji, Kung Yee Liang Johns Hopkins University

  2. Starting point: Genome wide association study (GWAS) of oral clefts • Cleft consortium supported by U01-DE-004425 (2007-2009) • Part of GENEVA collaboration • Murray (UIowa), Marazita (UPittsburgh), Munger (USU), Wilcox/Lie (NIEHS/UBergen) • Case-parent trio design to test for • Gene effects • Gene-environment interaction • Parent of origin effects

  3. Isolated, non-syndromic cleft cases & their parents from 13 populations

  4. Genome wide search turns up several “interesting” genes/regions Genome wide significant

  5. – but strength of evidence varies between Europeans & Asians

  6. Asian European CHR 8q24: Estimated genotypic relative risk (GRR) & 95%CI under an additive model obtained from a conditional logistic regression model for 78 SNPs in chr. 8q24 showing genome wide significance. The SNP showing the strongest signal was rs987525 (denoted by the star) is identical to that reported by 2 previous studies.

  7. Statistical signal from 78 SNPs in 8q24 and pairwise LD for A) CL/P case-parent trios of European ancestry; B) CL/P case-parent trios of Asian ancestry. B A

  8. Recognized Candidate Genes: IRF6

  9. Genes identified from GWAS • Statistical evidence requires follow-up • Direct investigation of genes & regions showing through sequencing • Next generation sequencing techniques are evolving rapidly

  10. Evaluating target capture for Next Gen Sequencing • Long range PCR techniques • We sequenced 40kb of IRF6 in 4 individuals and compared results to SNP genotypes • Multiplex PCR (RainDance Technology) • 4000 exons for CEPH samples • Agilent Sure Select (RNA baits  55K per assay for 2Mb of sequence) • DNA hybridization chip (Febit, Germany  500kb-1Mb)

  11. RainDance Technology Chr. 1 SNPs Comparing sequence to 1000 genomes genotypes & sequence

  12. Magnified view of RDT results

  13. MAFB MAFB on chr 20q11: A total 18 SNPs in the 3’UTR 20kb from MAFB showed genome wide significance (left). Estimated genotypic relative risk (GRR) & 95%CI under an additive model are shown over the region of signal.

  14. ABCA4 ABCA4 on chr 1q22 spans 150kb & showed multiple SNPs attaining genome wide significance ( left). Estimated GRR from a conditional logistic regression model & 95%CI for each SNP in this region.

  15. Hopkins FaceBase Project • Follow genes of interest by Next Gen Sequencing • This will include • Genes controlling risk alone • Genes involved in GxE interaction with common maternal exposures • Genes exhibiting parent-of-origin effects that may represent genomic imprinting • Analyze copy number variants using monomorphic markers in regions of CNV available from this marker panel

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