Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24

Abstract

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 x 10(-24). The odds ratio was 2.57 (95% CI = 2.02-3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88-9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

“…The allelic frequencies for all the tested SNPs in control group (Table 1) did not differ significantly from an- other publicly available data on Caucasian populations (http://www.ensembl.org) and were also similar to the frequencies reported from other case-control studies conducted on Central European populations 10,12,19,20 . With respect to allele distributions, the significant associations with nsCL/P risk, persisting even after Bonferroni correction for multiple comparisons, were found for SNPs at the 1q32, 8q24 and 17q22 loci.…”

“…The GWAS in Europeans also identified one of the most robust nsCL/P susceptibility loci at chromosome 8q24 (ref. [11][12][13] ), principally tagged by SNP rs987525. Additional significant GWAS signals in the European populations 14 were detected at loci 10q25 and 17q22, SNPs rs7078160 at 10q25 and rs227731 at 17q22 being the strongest susceptibility markers.…”

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

“…When considered as individual tests, they are also capable of detecting risk alleles that do not exhibit PofO effects, although with reduced power compared with the conventional TDT. For example, as can be seen in Figure 2, previously identified OFC risk loci such as the 8q24 locus 5 were detected, but as these show significant P-values in both the MAT and PAT tests strong PofO effects at these markers can be excluded. Therefore, a reasonable In bold: SNPs that pass our discovery criteria of Po1 Â 10 À5 and show and Pr0.01 in the replication cohort.…”

“…Non-syndromic clefts are divided into two categories on the basis of epidemiological and embryological research findings: (i) cleft lip with or without cleft palate (CL/P) and (ii) cleft palate only (CPO). 3,4 Although genome-wide association studies (GWAS) have identified several genetic loci associated with risk oral clefting, [5][6][7] there is significant evidence of other biological factors contributing to etiology of OFC. 8 These may include parent-of-origin (PofO) effects such as imprinting, 9 and other effects such as maternal-fetal interactions.…”

Genome-wide Association Studies

“…Several more GWAS studies of these oral health outcomes, plus periodontal disease, dental fear, and saliva flow rate, are currently under way. Notable associations for oral health outcomes include the PVT1/GSDMC locus on chromosome 8q24, which was independently identified in three GWAS studies of non-syndromic cleft lip with or without cleft palate (CL/P; Birnbaum et al, 2009;Grant et al, 2009;Beaty et al, Poor-quality DNA samples may need to be recollected and/or replaced. (F) Substantial data cleaning, quality checking, and pre-processing are necessary, including rigorous investigations of the following items: SNP call rates to identify/exclude poorly genotyped variants, genotype batch effects to detect genotyping artifacts, Hardy-Weinberg equilibrium to identify poorly performing SNPs, relationship testing to verify known kinships and detect cryptic kinships, gender tests to help identify sample swaps, and tests for "connectivity" to identify sample contamination.…”