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Study Description

Oral clefts represent the most common group of craniofacial birth defects in humans, and include cleft lip with or without cleft palate (CL/P) and cleft palate (CP). 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, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrient intake. This consortium pulls together a very large collection of cases and their parents from multiple populations, and offers a unique opportunity to expand the search for genes controlling risk to the genome wide level.

The specific aims are:

  1. To conduct a genome wide analysis on 2000+ case-parent trios ascertained through a case with isolated, non-syndromic CL/P or CP to test for linkage and disequilibrium. Initial analysis will consist of individual tests for gene effects while simultaneously testing for GxE interaction with common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (which have all been implicated as environmental risk factors for oral clefts).
  2. To use haplotypes in tests for GxE interaction incorporating population specific estimates. Since haplotype frequencies vary among populations, trios will be assigned haplotypes in a stratified estimation and then a pooled test statistic will be constructed.
  3. To test for interaction between SNPs in different genes showing evidence of influencing risk in a test for GxG interaction.
  4. To test for interaction between genes and maternal biomarkers using trios from Utah where measures of plasma folate, vitamin B-6, homocysteine and zinc in mothers are available.

This study is part of the Gene Environment Association Studies initiative (GENEVA,, which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to oral clefts through large-scale genome-wide association studies of well-characterized cases and their parents from multiple populations. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  • Study Types: Case Set, Parent-Offspring Trios
  • dbGaP estimated ancestry components using GRAF-pop
  • Number of study subjects that have individual level data available through Authorized Access: 7507

Authorized Access
Publicly Available Data (Public ftp)

Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.

In the course of routine data cleaning and data analyses, investigators may incidentally identify genetic abnormalities that might influence the clinical care of an individual. These statements and recommendations have been developed to help investigators when they are informed of any such incidental findings.

  1. GENEVA Statement on Incidental Findings
  2. GENEVA Aneuploidy Reference Table
  3. GENEVA Pharmacogenetic Variants Reference Table

Study Inclusion/Exclusion Criteria

Cases were identified as having an isolated, non-syndromic oral cleft (CL, CLP or CP) from a number of different populations, generally through a treatment center or population based registry. Parents were asked to give consent for the case, although assent was sought from children when appropriate. Parents were interviewed regarding family history and maternal exposures during the peri-conceptual period (3 months prior to conception through the first trimester). Exposure to maternal smoking, alcohol consumption and multivitamin use were covered in all populations, and exposure to environmental tobacco smoke during pregnancy was available in some populations.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Genotyping Illumina Human610_Quadv1_B 601273 1048904
Study History

This consortium was formed in 2006 in response to the Genes and Environment Imitative (GEI), a NIH wide initiative. The participants are all experiences researchers in the genetics and genetic epidemiology of oral clefts, and each has foreign collaborators contributing samples to this study. Case-parent trios were recruited from over 12 separate populations under similar research protocols, and individual IRBs at each institution reviewed and approved submission of coded data to dbGaP as part of this research project. The primary US research groups are:

  • Johns Hopkins (Beaty, TH, PI) which brought in samples from a multicenter international study supported by R01-DE-014881 with participating recruitment sites in Singapore (Chong, S and Yeow, V, site PIs), Taiwan (Wu-Chou, YH, site PI), and 3 sites in Peoples' Republic of China (Wang, H, site PI, Shandong Providence; Huang, S, site PI and Ye, X, Wuhan; and Shi, B, Chengdu), plus Korea (Jee, SH).
  • University of Iowa (Murray, JC, PI) which contributed samples from Denmark (Christensen, K) and the Philippines.
  • Utah State University (Munger, RG, PI).
  • University of Pittsburg (Marazita, ML, PI).
  • NIEHS and University of Bergen (Wilcox, A and Lie, RT).

Selected publications
Diseases/Traits Related to Study (MESH terms)
Links to Related Resources
Authorized Data Access Requests
Study Attribution