During the initial period of R01-DE-014581 (2003-2008), we successfully conducted a multi-center, international study on the genetic etiology of oral clefts (including cleft lip, CL;cleft lip and palate, CLP;and cleft palate, CP) by recruiting cases from 5 sites (Maryland, Singapore, Taiwan, and 2 sites in China). We have assembled 1497 case-parent trios, and successfully genotyped 5412 single nucleotide polymorphic (SNP) markers in candidate genes and candidate pathways on subsets of trios. Several genes have been identified as influencing risk to oral clefts (including some recognized candidate genes and some novel ones), and some genes show distinct parent-of-origin effects and potential interaction with common environmental risk factors. This competitive renewal application will extend and build upon our previous studies plus a genome wide association study (GWAS) from a consortium of our Hopkins group and 4 other groups. We propose 4 specific aims: 1) To compare our GWAS findings using case-parent trios with those of a German case-control study through combined analysis followed by fine mapping of new case-parent trios from the US, Asia, Germany and Ireland. 2) To consider models for assessing gene-environment (GxE) interactions with common maternal exposures (maternal smoking, alcohol consumption and vitamin supplementation) by analyzing the entire genome wide SNP array using our GWAS case-parent trios and the German cases. We will also collaborate with Dr. Munger of Utah State University (long time consultant to this project) to measure levels of vitamin B12 and methylmalonic acid in serum samples from mothers of cleft cases to evaluate biological models relevant to one carbon metabolism and DNA methylation. 3) To further investigate genes showing evidence of parent- of-origin effects (which may reflect genetic imprinting) by extending case families to include grandparents in 3 populations (Maryland, Taiwan and Singapore). We will also test for differential methylation patterns in selected genes identified during this study. 4) We will conduct deep resequencing studies of genes showing evidence of acting alone, only in the presence of environmental exposures or only when transmitted through one parent to identify all variants in genes and their cis-regulatory regions, especially rare variants, that may control risk to oral clefts.

Public Health Relevance

This project will combine data from two genome wide studies of non-syndromic oral clefts (cleft lip, cleft lip &palate, and cleft palate) to identify genes that may act alone in controlling risk, genes that may interact with common maternal exposures (maternal smoking, alcohol consumption and vitamin use), and genes that show evidence of different transmission from mothers and fathers which may reflect imprinting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014581-08
Application #
8107649
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Harris, Emily L
Project Start
2002-03-01
Project End
2014-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
8
Fiscal Year
2011
Total Cost
$674,732
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
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
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate. Hum Genet 136:275-286
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
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
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 :
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
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
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
Wise, Alison S; Shi, Min; Weinberg, Clarice R (2016) Family-Based Multi-SNP X Chromosome Analysis Using Parent Information. Front Genet 7:20
Leslie, E J; Koboldt, D C; Kang, C J et al. (2016) IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families. Clin Genet 90:28-34

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