Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia

PLOS ONE, Apr 2009

Background Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads). Methodology/Principal Findings We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM. Conclusion/Significance Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting—with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field.

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Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia

et al. (2009) Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia. PLoS ONE 4(4): e5385. doi:10.1371/journal.pone.0005385 Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia Astanand Jugessur 0 Min Shi 0 H akon Kristian Gjessing 0 Rolv Terje Lie 0 Allen James Wilcox 0 Clarice Ring Weinberg 0 Kaare Christensen 0 Abee Lowman Boyles 0 Sandra Daack-Hirsch 0 Truc Nguyen Trung 0 Camilla Bille 0 Andrew Carl Lidral 0 Jeffrey Clark Murray 0 Syed A. Aziz, Health Canada, Canada 0 1 Craniofacial Development, Musculoskeletal Disorders, Murdoch Childrens Research Institute, Royal Children's Hospital , Parkville , Australia , 2 Biostatistics Branch , National Institute of Environmental Health Sciences (NIEHS) , Research Triangle Park, Durham , North Carolina, United States of America, 3 Department of Epidemiology (EPAM), Norwegian Institute of Public Health , Oslo , Norway , 4 Section for Epidemiology and Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen , Bergen , Norway , 5 Medical Birth Registry of Norway, Norwegian Institute of Public Health , Bergen, Norway, 6 Epidemiology Branch , National Institute of Environmental Health Sciences (NIEHS) , Research Triangle Park, Durham , North Carolina, United States of America, 7 Department of Epidemiology, University of Southern Denmark , Odense, Denmark , 8 College of Nursing, University of Iowa , Iowa City , Iowa, United States of America, 9 Departments of Pediatrics, Epidemiology and Biological Sciences, University of Iowa , Iowa City, Iowa , United States of America Background: Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads). Methodology/Principal Findings: We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM. Conclusion/Significance: Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting-with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field. - Funding: CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, Contract Number N01-HG65403. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences; by NIH grants DE08559, P60 DE13076, NIH P30 ES05605, and RO1 DE-11948-04; and by the Norwegian Research Council. We also thank the US National Institute of Dental and Craniofacial Research (NIDCR) for underwriting a significant proportion of the genotyping costs by CIDR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. With an average worldwide prevalence of 1.2/1000 live births, facial clefts are the most common craniofacial birth defects and one of the most common major types of defect in humans [1]. The extensive surgical, dental and speech involvement, as well as potential psychological sequelae, underscore the importance of elucidating the causes of these complex facial defects. Analysis of familial recurrence, segregation, and concordance in twins have provided compelling evidence for a very strong genetic component to clefting [2]. In Norway, for example, the risk among first-degree relatives is approximately 40-fold higher than in the general population [3]. However, the joi (...truncated)


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Astanand Jugessur, Min Shi, Håkon Kristian Gjessing, Rolv Terje Lie, Allen James Wilcox, Clarice Ring Weinberg, Kaare Christensen, Abee Lowman Boyles, Sandra Daack-Hirsch, Truc Nguyen Trung, Camilla Bille, Andrew Carl Lidral, Jeffrey Clark Murray. Genetic Determinants of Facial Clefting: Analysis of 357 Candidate Genes Using Two National Cleft Studies from Scandinavia, PLOS ONE, 2009, 4, DOI: 10.1371/journal.pone.0005385