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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

Marazita, ML and Lidral, AC and Murray, JC and Field, LL and Maher, BS and Goldstein McHenry, T and Cooper, ME and Govil, M and Daack-Hirsch, S and Riley, B and Jugessur, A and Felix, T and Morene, L and Mansilla, MA and Vieira, AR and Doheny, K and Pugh, E and Valencia-Ramirez, C and Arcos-Burgos, M (2009) 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. Human Heredity, 68 (3). 151 - 170. ISSN 0001-5652

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Abstract

Objectives: 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. © 2009 S. Karger AG, Basel.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Marazita, MLmarazita@pitt.eduMARAZITA
Lidral, AC
Murray, JC
Field, LL
Maher, BS
Goldstein McHenry, T
Cooper, ME
Govil, M
Daack-Hirsch, S
Riley, B
Jugessur, A
Felix, T
Morene, L
Mansilla, MA
Vieira, ARarv11@pitt.eduARV11
Doheny, K
Pugh, E
Valencia-Ramirez, C
Arcos-Burgos, M
Date: 1 July 2009
Date Type: Publication
Journal or Publication Title: Human Heredity
Volume: 68
Number: 3
Page Range: 151 - 170
DOI or Unique Handle: 10.1159/000224636
Schools and Programs: School of Dental Medicine > Dental Science
Refereed: Yes
ISSN: 0001-5652
MeSH Headings: Chromosome Mapping; Chromosomes, Human--genetics; Cleft Lip--genetics; Cleft Palate--genetics; Genetic Linkage; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Humans; Phenotype; Polymorphism, Single Nucleotide
Other ID: NLM NIHMS95000, NLM PMC2709160
PubMed Central ID: PMC2709160
PubMed ID: 19521098
Date Deposited: 20 Sep 2012 20:05
Last Modified: 20 Feb 2020 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/14325

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