INTERNATIONAL GENETIC EPIDEMIOLOGY OF ORAL CLEFTS

Summary

Principal Investigator: Terri H Beaty
Abstract: DESCRIPTION (provided by investigator): 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.
Funding Period: 2002-03-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts
    J W Park
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
    J Med Genet 43:598-608. 2006
  2. pmc Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate
    Tao Wu
    Peking University School of Public Health, Beijing, China
    Birth Defects Res A Clin Mol Teratol 94:76-83. 2012
  3. pmc Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts
    Min Shi
    Biostatistics Branch, NIEHS NIH, Durham, North Carolina, USA
    Am J Med Genet A 158:784-94. 2012
  4. pmc ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population
    Hong Wang
    Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    Chin Med J (Engl) 125:476-80. 2012
  5. pmc Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans
    Tanda Murray
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
    Genet Epidemiol 36:392-9. 2012
  6. pmc BMP4 was associated with NSCL/P in an Asian population
    Qianqian Chen
    Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
    PLoS ONE 7:e35347. 2012
  7. pmc Incorporating genotype uncertainties into the genotypic TDT for main effects and gene-environment interactions
    Margaret A Taub
    Department of Biostatistics, Johns Hopkins University, 615 N Wolfe Street, Baltimore, MD 21205 2179, USA
    Genet Epidemiol 36:225-34. 2012
  8. pmc Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations
    Ardeshir Omoumi
    Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    Eur J Hum Genet 21:1436-41. 2013
  9. pmc X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts
    Poorav J Patel
    Johns Hopkins University, Baltimore, MD 21205 2103, USA
    Eur J Oral Sci 121:63-8. 2013
  10. pmc Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study
    T H Beaty
    Department of Epidemiology, School of Public Health, Johns Hopkins University, 615N Wolfe St, Baltimore, MD 21205, USA
    Hum Genet 132:771-81. 2013

Detail Information

Publications29

  1. pmc High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts
    J W Park
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
    J Med Genet 43:598-608. 2006
    ..Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously...
  2. pmc Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate
    Tao Wu
    Peking University School of Public Health, Beijing, China
    Birth Defects Res A Clin Mol Teratol 94:76-83. 2012
    ..Our results suggest genetic variation in RUNX2 may influence susceptibility to CL/P through interacting with ETS...
  3. pmc Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts
    Min Shi
    Biostatistics Branch, NIEHS NIH, Durham, North Carolina, USA
    Am J Med Genet A 158:784-94. 2012
    ..Thus, the most promising SNPs identified by this study may still be worth further investigation...
  4. pmc ROR2 gene is associated with risk of non-syndromic cleft palate in an Asian population
    Hong Wang
    Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    Chin Med J (Engl) 125:476-80. 2012
    ..The aim of this study was to investigate the possible association between ROR2 gene and non-syndromic oral clefts...
  5. pmc Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans
    Tanda Murray
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA
    Genet Epidemiol 36:392-9. 2012
    ....
  6. pmc BMP4 was associated with NSCL/P in an Asian population
    Qianqian Chen
    Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
    PLoS ONE 7:e35347. 2012
    ..The aim of the current study was to test for possible association between markers in and around the BMP4 gene and NSCL/P in Asian and Maryland trios...
  7. pmc Incorporating genotype uncertainties into the genotypic TDT for main effects and gene-environment interactions
    Margaret A Taub
    Department of Biostatistics, Johns Hopkins University, 615 N Wolfe Street, Baltimore, MD 21205 2179, USA
    Genet Epidemiol 36:225-34. 2012
    ..We find that by far the least biased results are obtained when family structure is taken into account and currently recommend this approach in spite of its intense computational requirements...
  8. pmc Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations
    Ardeshir Omoumi
    Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    Eur J Hum Genet 21:1436-41. 2013
    ..This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface. ..
  9. pmc X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts
    Poorav J Patel
    Johns Hopkins University, Baltimore, MD 21205 2103, USA
    Eur J Oral Sci 121:63-8. 2013
    ....
  10. pmc Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study
    T H Beaty
    Department of Epidemiology, School of Public Health, Johns Hopkins University, 615N Wolfe St, Baltimore, MD 21205, USA
    Hum Genet 132:771-81. 2013
    ..Formal tests for gene-gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P...
  11. pmc Sensitive and specific detection of mosaic chromosomal abnormalities using the Parent-of-Origin-based Detection (POD) method
    Joseph D Baugher
    Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
    BMC Genomics 14:367. 2013
    ..Most mosaic alterations remain undetectable with current analytical approaches, although the presence of such alterations is increasingly implicated as causative for disease...
  12. pmc Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate
    Tao Wu
    Peking University Health Science Center, Beijing, China Johns Hopkins University, School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 9:e88088. 2014
    ....
  13. ncbi [Comparison of minor allele frequencies and haplotype frequencies for single nucleotide polymorphisms in ROR2 gene using HapMap data for Chinese Hans in Beijing and Yoruban in Ibadan in Nigeria]
    Hong Wang
    Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    Beijing Da Xue Xue Bao 43:785-91. 2011
    ..To provide basis for single nucleotide polymorphisms (SNPs) determination and analysis for ROR2 genes related etiologic studies in Chinese Hans in Beijing (CHB) and Yoruban in Ibadan in Nigeria (YRI) populations...
  14. pmc Rapid testing of SNPs and gene-environment interactions in case-parent trio data based on exact analytic parameter estimation
    Holger Schwender
    TU Dortmund University, 44221 Dortmund, Germany
    Biometrics 68:766-73. 2012
    ....
  15. pmc Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate
    Terri H Beaty
    School of Public Health, Johns Hopkins University, 615 N Wolfe St, Baltimore, Maryland, USA
    Genet Epidemiol 35:469-78. 2011
    ..8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP...
  16. ncbi Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations
    T H Beaty
    Johns Hopkins University, Baltimore, MD, USA
    Hum Genet 120:501-18. 2006
    ....
  17. pmc Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations
    Ji Wan Park
    Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA, and Department of Medical Research and Craniofacial Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
    Genet Med 9:219-27. 2007
    ..This study aimed to confirm the contribution of IRF6 to cleft lip with or without palate risk in additional Asian populations...
  18. pmc Differential parental transmission of markers in RUNX2 among cleft case-parent trios from four populations
    Jae Woong Sull
    Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA
    Genet Epidemiol 32:505-12. 2008
    ..Thus, RUNX2 appears to influence risk of CL/P through a parent-of-origin effect with excess maternal transmission...
  19. pmc Excess maternal transmission of markers in TCOF1 among cleft palate case-parent trios from three populations
    Jae Woong Sull
    Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Am J Med Genet A 146:2327-31. 2008
    ..136), analysis of haplotypes of rs2255796 and rs15251 suggested excess maternal transmission. Therefore, these data suggest TCOF1 may influence risk of cleft palate through a parent-of-origin effect...
  20. pmc Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations
    Jae Woong Sull
    Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea
    Eur J Hum Genet 17:831-9. 2009
    ..PAX genes may influence the risk of CL/P through maternal effects, possibly imprinting, which seems to be stronger among male cases...
  21. pmc Differential parental transmission of markers in BCL3 among Korean cleft case-parent trios
    Beyoung Yun Park
    Yonsei University School of Medicine, Seoul, Korea
    J Prev Med Public Health 42:1-4. 2009
    ..This study tests for an association between markers in BCL3 and isolated, non-syndromic CL/P using a case-parent trio design, while considering parent-of-origin effects...
  22. pmc Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms
    Jae Woong Sull
    Department of Epidemiology and Health Promotion, Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea
    Hum Genet 126:385-94. 2009
    ..Thus, TGFA appears to influence risk of CL/P through unconventional means with an apparent parent-of-origin effect (excess maternal transmission) and possible interaction with maternal exposures...
  23. pmc Association between IRF6 SNPs and oral clefts in West China
    Y Huang
    State Key Laboratory of Oral Disease, West China College of Stomatology, Sichuan University, Chengdu 610041, P R China
    J Dent Res 88:715-8. 2009
    ..Five specific haplotypes showed significant over- and under-transmission. These results further support a role for IRF6 variants in western Chinese populations...
  24. pmc Association between genes on chromosome 4p16 and non-syndromic oral clefts in four populations
    Roxann G Ingersoll
    Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, Baltimore, MD 21287, USA
    Eur J Hum Genet 18:726-32. 2010
    ..These two genes plus EVC2 also yielded suggestive evidence for linkage and disequilibrium among cleft palate trios. This analysis suggests that several genes, not just MSX1, in this region may influence risk of oral clefts...
  25. pmc A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4
    Terri H Beaty
    Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA
    Nat Genet 42:525-9. 2010
    ..Expression studies support a role for MAFB in palatal development...
  26. pmc Evidence of gene-environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate
    Tao Wu
    Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
    Hum Genet 128:401-10. 2010
    ..These results suggest IRF6 gene may influence risk of CL/P through interaction with multivitamin supplementation and ETS in the Chinese population...
  27. pmc Cleft lip and palate: understanding genetic and environmental influences
    Michael J Dixon
    Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK
    Nat Rev Genet 12:167-78. 2011
    ..These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research...
  28. pmc Inferring rare disease risk variants based on exact probabilities of sharing by multiple affected relatives
    Alexandre Bureau
    Centre de Recherche de l Institut Universitaire en Santé Mentale de Québec, G1J 2G3, Departement de Medecine sociale et preventive, Universite Laval, Quebec, G1V 0A6 Canada, Department of Biostatistics, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, PA 15219, Department of Pediatrics, School of Medicine, University of Iowa, IA 52242, USA, Institute of Human Genetics, University of Bonn, Bonn D 53127, Germany and Dr Hejazi Clinic, P O Box 2519, Riyadh 11461, Saudi ArabiaCentre de Recherche de l Institut Universitaire en Santé Mentale de Québec, G1J 2G3, Departement de Medecine sociale et preventive, Universite Laval, Quebec, G1V 0A6 Canada, Department of Biostatistics, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD 21224, Department of Oral Biology
    Bioinformatics 30:2189-96. 2014
    ....

Research Grants30

  1. Genetic Risk for Orofacial Clefts in the Folate/Homocysteine Pathway
    NICHOLAS MARINI; Fiscal Year: 2013
    ..This research plan capitalizes on an ongoing and successful collaboration that unites a unique combination of expertise for its execution. ..
  2. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  3. Genomic/Epigenomic Factors and Non-Syndromic Congenital Heart Defect Risk
    Charlotte A Hobbs; Fiscal Year: 2013
    ..Through our discoveries, we will contribute to a substantially richer understanding of the etiology of OHDs, providing a foundation for public health and clinical prevention and treatment strategies. ..
  4. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  5. Methods for Pathway Modeling with Application to Folate
    Duncan C Thomas; Fiscal Year: 2013
    ....
  6. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  7. Oral Clefts: Moving from Genome Wide Studies Toward Functional Genomics
    Terri H Beaty; Fiscal Year: 2013
    ....
  8. Beryllium: Exposure Immune and Genetic Mechanisms
    Lee S Newman; Fiscal Year: 2013
    ..The productivity and continuance demonstrate quality, commitment and ability to work together. PROGRAM AS INTERGRATED EFFORT ..
  9. NMR AND COMPUTATIONAL STUDIES OF BIOMOLECULES
    Gerhard Wagner; Fiscal Year: 2013
    ..We anticipate that the proposed research will continue to advance the capabilities of NMR for structural biology. ..
  10. Environment, The Perinatal Epigenome, and Risk for Autism and Related Disorders
    Andrew P Feinberg; Fiscal Year: 2013
    ..It will provide the first rigorous analysis of the relationship between nature and nurture in the human epigenome. ..