Many research groups have attempted to identify genetic loci contributing to the etiology of cleft lip with or without cleft palate (CL/P) with limited success to date. There have been several allelic associations identified in European Caucasian populations, and a few potentially linked markers; however, these results have not been consistent across study populations. It appears that the genetic contribution to the etiology of oral-facial clefting is complex, possibly heterogeneous, or possibly due to interacting effects of multiple loci. This proposal is a continuation of grant #1-R01-DE09886.
The aims of the first five years of the project were: to collect CL/P data from Shanghai, China (demographic, family histories from 2,000 CL/P probands, DNA from a subset of 100 multiplex families); to test genetic hypotheses and associations with covariates; and to genotype and test for linkage or association with candidate loci implicated in CL/P. We have successfully accomplished each of these specific aims on schedule. Notable results were: (1) an autosomal recessive major locus was the best-fit to the family data; (2) no association was found between CL/P and demographic factors; (3) there were significant associations between non-right-handedness and dermatoglyphic asymmetry and CL/P; (4) none of 71 candidate genes and flanking markers showed linkage or association in this Chinese sample, implying that different loci are involved in Asians than in Caucasians. The major goal of our research program remains to identify loci involved in CL/P in Asia. Because no positive results were found with the Caucasian candidates, we now propose to continue our project, expanding a genome-wide screen for loci involved in CL/P in Asia.
The specific aims of this continuation are to: (1) Increase the Chinese study sample by 40-50 families to increase the power of the Chinese families to detect linkage under heterogeneity (confirm family histories, obtain blood samples, extract DNA); (2) Genotype 1,270 study subjects from multiplex CL/P families (about 600 existing and 400 new Chinese individuals, and 270 existing Indian individuals) for a dense genome-wide panel of about 400 STRP markers (10cM apart)--Weber screening Set 8; (3) Assess linkage between CL/P and each marker using parametric two-point LOD scores and multipoint mapping, and also using the nonparametric SimIBD statistic; (4) Assess allelic association using the family-based AFBAC method; (5) Genotype additional markers in regions of possible linkage or association to confirm and refine any positive results; (6) Compare results between the two Asian populations--Caucasian (West Bengal) and non-Caucasian (Chinese).
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