Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families

Abstract

Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly. Birth prevalences range from 1/500 to 1/1,000 and are consistently higher in Asian populations than in populations of European descent. Therefore, it is of interest to determine whether the CL/P etiological factors in Asian populations differ from those in white populations. A sample of 36 multiplex families were ascertained through probands with CL/P who were from Shanghai. This is the first reported genome-scan study of CL/P in any Asian population. Genotyping of Weber Screening Set 9 (387 short tandem-repeat polymorphisms with average spacing approximately 9 cM [range 1-19 cM]) was performed by the Mammalian Genotyping Service of Marshfield Laboratory. Presented here are the results for the 366 autosomal markers. Linkage between each marker and CL/P was assessed by two-point and multipoint LOD scores, as well as with multipoint heterogeneity LOD scores (HLODs) plus model-free identity-by-descent statistics and the multipoint NPL statistic. In addition, association was assessed via the transmission/disequilibrium test. LOD-score and HLOD calculations were performed under a range of models of inheritance of CL/P. The following regions had positive multipoint results (HLOD > or =1.0 and/or NPL P< or =.05): chromosomes 1 (90-110 cM), 2 (220-250 cM), 3 (130-150 cM), 4 (140-170 cM), 6 (70-100 cM), 18 (110 cM), and 21 (30-50 cM). The most significant multipoint linkage results (HLOD > or =2.0; alpha=0.37) were for chromosomes 3q and 4q. Associations with P< or =.05 were found for loci on chromosomes 3, 5-7, 9, 11, 12, 16, 20, and 21. The most significant association result (P=.009) was found with D16S769 (51 cM).

Figure 1

Pedigree diagrams of 36 families from Shanghai

Figure 2

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 1, under the dominant model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented. The black rectangles denote chromosomal regions for which positive linkage results were found, by Prescott et al. (2000), in 92 affected sib pairs from England.

Figure 3

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 2, under the dominant model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented. The black rectangles denote chromosomal regions for which positive linkage results were found, by Prescott et al. (2000), in 92 affected sib pairs from England.

Figure 4

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 3, under the dominant model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented.

Figure 5

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 4, under the recessive model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented.

Figure 6

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 6, under the dominant model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented. The black rectangles denote chromosomal regions for which positive linkage results were found, by Prescott et al. (2000), in 92 affected sib pairs from England.

Figure 7

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 18, under the recessive model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented.

Figure 8

Results of multipoint analyses of genome-scan markers in 36 multiplex families from Shanghai, for chromosome 21, under the dominant model. Note that each multipoint analysis was performed under both dominant and recessive models of inheritance for CL/P; results under the model with the highest HLOD are presented.