Facebase kick off meeting nov 15 16 2009 bethesda
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FaceBase Kick-Off Meeting Nov 15-16, 2009 Bethesda PowerPoint PPT Presentation


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FaceBase Kick-Off Meeting Nov 15-16, 2009 Bethesda. Oral Clefts: Moving from Genome Wide Studies Toward Functional Genomics TH Beaty for Alan F Scott, Ingo Ruczinski, Hong Kai Ji, Kung Yee Liang Johns Hopkins University. Starting point: Genome wide association study (GWAS) of oral clefts.

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

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Facebase kick off meeting nov 15 16 2009 bethesda

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


Starting point genome wide association study gwas of oral clefts

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


Isolated non syndromic cleft cases their parents from 13 populations

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


Genome wide search turns up several interesting genes regions

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

Genome wide significant


But strength of evidence varies between europeans asians

– but strength of evidence varies between Europeans & Asians


Facebase kick off meeting nov 15 16 2009 bethesda

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.


Facebase kick off meeting nov 15 16 2009 bethesda

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


Recognized candidate genes irf6

Recognized Candidate Genes: IRF6


Genes identified from gwas

Genes identified from GWAS

  • Statistical evidence requires follow-up

  • Direct investigation of genes & regions showing through sequencing

  • Next generation sequencing techniques are evolving rapidly


Evaluating target capture for next gen sequencing

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)


Raindance technology chr 1 snps

RainDance Technology Chr. 1 SNPs

Comparing sequence to 1000 genomes genotypes & sequence


Magnified view of rdt results

Magnified view of RDT results


Facebase kick off meeting nov 15 16 2009 bethesda

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.


Facebase kick off meeting nov 15 16 2009 bethesda

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.


Hopkins facebase project

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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