Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results

ABSTRACT: Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P). Methods: We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results. Results: Significant (multipoint HLOD ≥3.2) or genome-wide-significant (HLOD ≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP. Conclusions: These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.

• Autores: Valencia Ramírez, Luz Consuelo; Arcos Burgos, Oscar Mauricio; Murray, Jeffrey; Field, Leigh; Maher, Brion; Goldstein McHenry, Toby; Cooper, Margaret E.; Govil, Manika; Daack Hirsch, Sandra; Riley, Bridget; Jugessur, Astanand; Felix, Temis; Morene, Lina; Mansilla, Adela; Vieira, Alexandre R.; Doheny, Kim; Pugh, Elizabeth; Maritza, Mary; Lidral, Andrew C.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2009
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/41528
• Acceso en línea: https://hdl.handle.net/10495/41528
• Palabra clave: Mapeo Cromosómico; Chromosome Mapping; Cromosomas Humanos - genética; Chromosomes, Human - genetics; Labio Leporino - genética; Cleft Lip - genetics; Fisura del Paladar - genética; Cleft Palate - genetics; Ligamiento Genético; Genetic Linkage; Predisposición Genética a la Enfermedad; Genetic Predisposition to Disease; Genoma Humano; Genome, Human; Estudio de Asociación del Genoma Completo; Genome-Wide Association Study; Fenotipo; Phenotype; Polimorfismo de Nucleótido Simple; Polymorphism, Single Nucleotide; https://id.nlm.nih.gov/mesh/D002874; https://id.nlm.nih.gov/mesh/D002877; https://id.nlm.nih.gov/mesh/D002971; https://id.nlm.nih.gov/mesh/D002972; https://id.nlm.nih.gov/mesh/D008040; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D015894; https://id.nlm.nih.gov/mesh/D055106; https://id.nlm.nih.gov/mesh/D010641; https://id.nlm.nih.gov/mesh/D020641
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc/2.5/co/