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.
OBJECTIVE
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 >or=3.2) or genome-wide-significant (HLOD >or=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.
Marazita
Mary L
ML
Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. marazita@pitt.edu
Lidral
Andrew C
AC
Murray
Jeffrey C
JC
Field
L Leigh
LL
Maher
Brion S
BS
Goldstein McHenry
Toby
T
Cooper
Margaret E
ME
Govil
Manika
M
Daack-Hirsch
Sandra
S
Riley
Bridget
B
Jugessur
Astanand
A
Felix
Temis
T
Morene
Lina
L
Mansilla
M Adela
MA
Vieira
Alexandre R
AR
Doheny
Kim
K
Pugh
Elizabeth
E
Valencia-Ramirez
Consuelo
C
Arcos-Burgos
Mauricio
M
D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide