Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts.
Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DE018993-01
Application #
7327307
Study Section
Special Emphasis Panel (ZHG1-HGR-P (M1))
Program Officer
Mcinnes, Pamela M
Project Start
2007-08-03
Project End
2009-05-31
Budget Start
2007-08-03
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$622,913
Indirect Cost
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Howe, Laurence J; Lee, Myoung Keun; Sharp, Gemma C et al. (2018) Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology. PLoS Genet 14:e1007501
Bureau, Alexandre; Begum, Ferdouse; Taub, Margaret A et al. (2018) Inferring disease risk genes from sequencing data in multiplex pedigrees through sharing of rare variants. Genet Epidemiol :
Liu, Dongjing; Schwender, Holger; Wang, Mengying et al. (2018) Gene-gene interaction between MSX1 and TP63 in Asian case-parent trios with nonsyndromic cleft lip with or without cleft palate. Birth Defects Res 110:317-324
Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor et al. (2017) Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing. Birth Defects Res 109:1030-1038
Carlson, Jenna C; Taub, Margaret A; Feingold, Eleanor et al. (2017) Identifying Genetic Sources of Phenotypic Heterogeneity in Orofacial Clefts by Targeted Sequencing. Birth Defects Res :
Wang, Mengying; Yuan, Yuan; Wang, Zifan et al. (2017) Prevalence of Orofacial Clefts among Live Births in China: A Systematic Review and Meta-Analysis. Birth Defects Res 109:1011-1019
Fu, Jack; Beaty, Terri H; Scott, Alan F et al. (2017) Whole exome association of rare deletions in multiplex oral cleft families. Genet Epidemiol 41:61-69
Liu, Dongjing; Wang, Hong; Schwender, Holger et al. (2017) Gene-gene interaction of single nucleotide polymorphisms in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without cleft palate in Chinese case-parent trios. Am J Med Genet A 173:1489-1494
Liu, Huan; Leslie, Elizabeth J; Carlson, Jenna C et al. (2017) Identification of common non-coding variants at 1p22 that are functional for non-syndromic orofacial clefting. Nat Commun 8:14759
Xiao, Yanzi; Taub, Margaret A; Ruczinski, Ingo et al. (2017) Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios. Genet Epidemiol 41:244-250

Showing the most recent 10 out of 57 publications