Cleft lip with or without cleft palate (CL/P) is a common birth defect. Previous studies have indicated that CL/P is a complex trait that is caused by a combination of genetic and environmental factors. This complexity has limited studies, such that disease mutations have only been identified in one unique family. It is also unlikely that all disease loci have been identified. The overall objective of this project is to identify disease genes involved in nonsyndromic CL/P by applying new multistaged linkage and linkage disequilibrium (LD) strategies to affected relative pairs and extended pedigrees. This multistage approach, which has not yet been applied to CL/P, is very powerful in that no prior knowledge about the involved genetic or biological processes is needed. Hypotheses to be tested: Nonsyndromic CL/P is caused by Genetic Variants at one or more loci. To test this hypothesis, CL/P families with both multiple affected members and mother/father and affected child trios will be recruited from a variety of clinical centers including: Columbus, OH; Medellin, Colombia SA; Seattle, WA; Pittsburgh; and Finland as well as smaller centers including Cleveland (Dr. Nat Robin); San Francisco (Dr. Ed Lammer) and San Diego (Dr. Marilyn Jones). The multiplex families will be the basis for initially evaluating candidate genes to test the above hypothesis using the genetic tools of linkage and linkage disequilibrium to reject (exclude) or provide evidence for support (i.e. linkage) the hypotheses. A 10 cM genome-wide screen will also be performed to find additional loci. Positive loci will be further evaluated by a combination of multipoint, multi-locus and TDT/association analyses using more densely spaced markers. The heritage of the Colombia and Finland populations have led to unique population structures that are advantageous for finding disease genes for complex traits. Comparison of these populations to the outbred US population will provide important information regarding the genetic diversity leading to CL/P. The power initially (will be sufficient to identify loci of moderate or major risk (relative risks greater than 2.0) and during the project, power will increase to be able to identify minor loci (relative risks greater than 1.5). It will be through multi- center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P will be identified. Ultimately, this will further the understanding of normal and abnormal craniofacial development, such that therapies to prevent CL/P can be developed and implemented.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE014667-01
Application #
6496096
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Canto, Maria Teresa
Project Start
2001-09-15
Project End
2005-06-30
Budget Start
2001-09-15
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$324,486
Indirect Cost
Name
University of Iowa
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Cox, Liza L; Cox, Timothy C; Moreno Uribe, Lina M et al. (2018) Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate. Am J Hum Genet 102:1143-1157
Shaffer, John R; LeClair, Jessica; Carlson, Jenna C et al. (2018) Association of low-frequency genetic variants in regulatory regions with nonsyndromic orofacial clefts. Am J Med Genet A :
Carlson, Jenna C; Nidey, Nichole L; Butali, Azeez et al. (2018) Genome-wide interaction studies identify sex-specific risk alleles for nonsyndromic orofacial clefts. Genet Epidemiol 42:664-672
Howe, B J; Cooper, M E; Wehby, G L et al. (2017) Dental Decay Phenotype in Nonsyndromic Orofacial Clefting. J Dent Res 96:1106-1114
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2017) Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate. Am J Med Genet A 173:1531-1538
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
Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R et al. (2016) A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13. Hum Mol Genet 25:2862-2872
Lidral, Andrew C; Liu, Huan; Bullard, Steven A et al. (2015) A single nucleotide polymorphism associated with isolated cleft lip and palate, thyroid cancer and hypothyroidism alters the activity of an oral epithelium and thyroid enhancer near FOXE1. Hum Mol Genet 24:3895-907
Howe, B J; Cooper, M E; Vieira, A R et al. (2015) Spectrum of Dental Phenotypes in Nonsyndromic Orofacial Clefting. J Dent Res 94:905-12
Jugessur, Astanand; Shi, Min; Gjessing, HÃ¥kon Kristian et al. (2009) Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia. PLoS One 4:e5385

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