Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35

Abstract

Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD]=6.6). In addition, meta-analyses with the addition of results from 186 more families (six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P=.0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder.

Figure A1

Summary of the 10-cM genome scan of CL/P in the CIDR-7 studies. A–V, Summed multipoint HLOD plots for the autosomes, under the best genetic model for CL/P on that chromosome (dominant or recessive). W, Plot of the maximum summed two-point LOD scores on the X chromosome (θ at the peak LOD was 0.30).

Figure A2

Graphs of the MRMSs for all chromosomes analyzed in the 13 CL/P-study populations. These graphs summarize the process of repeating the GSMA analyses, shifting the bins to narrow the region of potential involvement in CL/P. For those chromosomes with GSMA/MRMS P values ⩽.05, the dashed vertical lines indicate the 10-cM MRMS. A–V, Autosomes. W, X chromosome.

Figure A3

Graphs of GSMA results by population subgroup (all, East Asian, white, or “other”). The results from the GSMA procedure that had the most significant result (i.e., of the three rebinned GSMA procedures) for each subpopulation are depicted. A–V, Autosomes. W, X chromosome.

Figure 1

Summary of the 10-cM genome scan of CL/P in the CIDR-7 studies. A, Summary of the maximum summed multipoint HLOD for each chromosome, under both dominant (DOM) and recessive (REC) genetic models for CL/P. B–F, Summed multipoint HLOD plots for each chromosome that had a maximum summed HLOD ⩾3.2 (under the best genetic model for each chromosome).

Figure 2

GSMA of 13 CL/P-study populations. Depicted are the R_avg for each of the 130 bins, across all chromosomes. The horizontal lines indicate the R_avg values corresponding to empirical P values of .05 and .01, as determined by simulation.

Figure 3

Graphs of the MRMSs for the six chromosomes with the most significant GSMA/MRMS results for the 13 CL/P-study populations. These graphs summarize the MRMS process, repeating the GSMA with bin shifting to narrow the statistically significant region. The dashed vertical lines indicate the 10-cM MRMS for each chromosome. A–F, Graph of chromosomes 1, 2, 6, 14, 17, and 18, respectively.

Figure 4

Diagram of chromosome 9q21, with one- and two-LOD support intervals and candidate genes depicted