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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, Mary L; Lidral, Andrew C; Murray, Jeffrey C; Field, L. Leigh; Maher, B.S.; Goldstein McHenry, T.; Cooper, Margaret E.; Govil, M.; Daack-Hirsch, Sandy; Riley, B.; Arcos-Burgos, Mauricio (Oscar)

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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...[Show more]

dc.contributor.authorMarazita, Mary L
dc.contributor.authorLidral, Andrew C
dc.contributor.authorMurray, Jeffrey C
dc.contributor.authorField, L. Leigh
dc.contributor.authorMaher, B.S.
dc.contributor.authorGoldstein McHenry, T.
dc.contributor.authorCooper, Margaret E.
dc.contributor.authorGovil, M.
dc.contributor.authorDaack-Hirsch, Sandy
dc.contributor.authorRiley, B.
dc.contributor.authorArcos-Burgos, Mauricio (Oscar)
dc.date.accessioned2015-12-13T22:45:40Z
dc.identifier.issn0001-5652
dc.identifier.urihttp://hdl.handle.net/1885/79900
dc.description.abstractObjectives: 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.
dc.publisherS Karger AG
dc.sourceHuman Heredity
dc.subjectKeywords: interferon regulatory factor 6; article; chromosome 12p; chromosome 14q; chromosome 16q; chromosome 1q; chromosome 2p; chromosome 3q; chromosome 9q; cleft lip; cleft lip palate; controlled study; FOXE1 gene; gene; gene mapping; genetic analysis; genetic a Association; Cleft lip; Cleft palate; FOXE1; Genetics; IRF6; Linkage; WFDR
dc.titleGenome 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
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume68
dc.date.issued2009
local.identifier.absfor060408 - Genomics
local.identifier.ariespublicationf5625xPUB8262
local.type.statusPublished Version
local.contributor.affiliationMarazita, Mary L, University of Pittsburgh
local.contributor.affiliationLidral, Andrew C, University of Iowa
local.contributor.affiliationMurray, Jeffrey C, University of Iowa
local.contributor.affiliationField, L. Leigh, University of British Columbia
local.contributor.affiliationMaher, B.S., Virginia Commonwealth University
local.contributor.affiliationGoldstein McHenry, T., University of Pittsburgh
local.contributor.affiliationCooper, Margaret E., University of Pittsburgh
local.contributor.affiliationGovil, M., University of Pittsburgh
local.contributor.affiliationDaack-Hirsch, Sandy, University of Iowa
local.contributor.affiliationRiley, B., New York University School of Medicine
local.contributor.affiliationArcos-Burgos, Mauricio (Oscar), College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue3
local.bibliographicCitation.startpage151
local.bibliographicCitation.lastpage170
local.identifier.doi10.1159/000224636
dc.date.updated2016-02-24T09:41:13Z
local.identifier.scopusID2-s2.0-65549128464
CollectionsANU Research Publications

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