Oral clefts are among the most common birth defects, estimated at 1 per 600-700 livebirths worldwide, and in terms of medical care, create a major public health burden for both affected children and their families. As part of the project """"""""International Genetic Epidemiology of Oral Clefts"""""""" (TH Beaty, PI) we conducted a genome wide association study (GWAS) to identify genes influencing risk to oral clefts, either directly, or through interaction with common maternal exposures, using case-parent trios assembled from an international consortium (""""""""International Consortium to Identify Genes &Interactions Controlling Oral Clefts""""""""). The ongoing analyses and initial results from our GWAS have raised several unanticipated questions. In addition, recent methodological developments (by our group, and others) allow us to regard some of the originally posed questions from novel vantage points, and offer opportunities for more powerful approaches. We therefore propose the development of novel statistical techniques, and to carry additional analyses on maternal exposure and the available genome scan data from more than 2000 complete case-parent trios, to further investigate the genetic and environmental risk factors for oral clefts. In particular, we propose to compare the performance of several publicly available algorithms with the ultimate goal to improve the delineation of de novo copy number variants in the affected oral clefts probands, to carry out comprehensive analyses for gene-gene and gene-environment interactions using novel genome-wide and candidate gene approaches, and to devise a fast and efficient case-parent trio association test for imputed genotypes.

Public Health Relevance

Oral clefts are among the most common birth defects, estimated at 1 per 600-700 livebirths worldwide, and in terms of medical care, create a major public health burden for both affected children and their families. We propose the development of novel statistical techniques and additional analyses on maternal exposure and genome scan data from more than 2000 complete case-parent trios, to investigate the genetic and environmental risk factors for oral clefts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE021437-02
Application #
8294546
Study Section
Special Emphasis Panel (ZDE1-MH (14))
Program Officer
Harris, Emily L
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$239,231
Indirect Cost
$89,231
Name
Johns Hopkins University
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Younkin, Samuel G; Scharpf, Robert B; Schwender, Holger et al. (2015) A genome-wide study of inherited deletions identified two regions associated with nonsyndromic isolated oral clefts. Birth Defects Res A Clin Mol Teratol 103:276-83
Schwender, Holger; Li, Qing; Neumann, Christoph et al. (2014) Detecting disease variants in case-parent trio studies using the bioconductor software package trio. Genet Epidemiol 38:516-22
Younkin, Samuel G; Scharpf, Robert B; Schwender, Holger et al. (2014) A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk. BMC Genet 15:24
Neumann, Christoph; Taub, Margaret A; Younkin, Samuel G et al. (2014) Analytic power and sample size calculation for the genotypic transmission/disequilibrium test in case-parent trio studies. Biom J 56:1076-92
Li, Qing; Schwender, Holger; Louis, Thomas A et al. (2013) Efficient simulation of epistatic interactions in case-parent trios. Hum Hered 75:12-22
Scharpf, Robert B; Beaty, Terri H; Schwender, Holger et al. (2012) Fast detection of de novo copy number variants from SNP arrays for case-parent trios. BMC Bioinformatics 13:330
Zhang, Tian-Xiao; Beaty, Terri H; Ruczinski, Ingo (2012) Candidate pathway based analysis for cleft lip with or without cleft palate. Stat Appl Genet Mol Biol 11:
Taub, Margaret A; Schwender, Holger; Beaty, Terri H et al. (2012) Incorporating genotype uncertainties into the genotypic TDT for main effects and gene-environment interactions. Genet Epidemiol 36:225-34
Schwender, Holger; Taub, Margaret A; Beaty, Terri H et al. (2012) Rapid testing of SNPs and gene-environment interactions in case-parent trio data based on exact analytic parameter estimation. Biometrics 68:766-73