Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate

Abstract

Nonsyndromic cleft lip with or without a cleft palate (NSCL/P) is among the most common human congenital birth defects and imposes a substantial physical and financial burden on affected individuals. Here, we conduct a case-control-based GWAS followed by two rounds of replication; we include six independent cohorts from China to elucidate the genetic architecture of NSCL/P in Chinese populations. Using this combined analysis, we identify a new locus at 16p13.3 associated with NSCL/P: rs8049367 between CREBBP and ADCY9 (odds ratio ¼ 0.74, P ¼ 8.98 Â 10 À 12 ). We confirm that the reported loci at 1q32.2, 10q25.3, 17p13.1 and 20q12 are also involved in NSCL/P development in Chinese populations. Our results provide additional evidence that the rs2235371-related haplotype at 1q32.2 could play a more important role than the previously identified causal variant rs642961 in Chinese populations. These findings provide information on the genetic basis and mechanisms of 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

“…Recent studies have reported association of nsCL/P with many loci throughout the genome [11][12][13][14][39][40][41][42] . Replication of those results on various populations and the investigation of mechanisms by which these variants influence cleft susceptibility are crucial for better understanding of genetic architecture of nsCL/P.…”

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

“…Lack of statistical power due to sample size and low MAF of the genotyped SNPs in Africans could also be possible reasons. For example, rs2235371-an SNP of IRF6 that is in high-linkage disequilibrium and the same locus as rs642961 and that has been associated with NSCL/P among mostly Asians (Sun et al 2015) and in some Europeans (Zucchero et al 2004)-does not exist in the African population (http://browser.1000genomes.org/index.html). It is also possible that even when no associations are detected between reported loci and NSOFCs, potentially pathogenic variants may be observed in NSOFC cases.…”

“…A meta-analysis revealed additional NSCL/P susceptibility loci: THADA, SPRY2, 15q22.2 (TPM1), and 1p36 (PAX7; Ludwig et al 2012). Recently, a GWAS involving Asians implicated 16p13.3 (ADCY9; Sun et al 2015) in the etiology of NSCL/P, whereas a GWAS involving dogs and a Guatemalan population gave a suggestive association for ADAMTS20 (Wolf et al 2015).…”

Variantes genéticas de risco às fissuras orofaciais

“…On the other hand, we diminish the relevance of IRF6 SNP rs642961 in susceptibility to NSCL/P in our population. Our results are consistent with recent findings that suggest that the association observed for IRF6 may be driven by other variants (Sun et al, 2015), even though a functional role has been attributed to this variant . Finally, we also reported, for the first time in our population, the association of a marker in 20q12 region.…”

“…Moreover, it confirmed the 8q24 locus as the strongest association in NSCL/P (Box 1). Recently, (Sun et al, 2015) conducted the fifth GWAS on NSCL/P, the first on a totally non-European sample (the Chinese population). A new susceptibility locus was revealed in this study (16p13), reinforcing the importance of testing populations other than Europeans.…”