Elsevier

The Journal of Pediatrics

Volume 155, Issue 6, December 2009, Pages 909-913
The Journal of Pediatrics

Original Article
A Genome-Wide Association Study Identifies a Locus for Nonsyndromic Cleft Lip with or without Cleft Palate on 8q24

https://doi.org/10.1016/j.jpeds.2009.06.020Get rights and content

Objective

To identify, in a non-hypothesis manner, novel genetic factors associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P).

Study design

We performed a genome-wide association study in a pediatric cohort of European decent consisting of 111 NSCL/P cases and 5951 control subjects. All subjects were consecutively recruited from the Greater Philadelphia area from 2006 to 2009. High throughput genome-wide single nucleotide polymorphism genotyping was carried out with the Illumina Infinium II HumanHap550 BeadChip technology.

Results

We observed association at the genome-wide significance level with SNP rs987525 at a locus on 8q24, which harbors no characterized genes to date (P = 9.18 × 10−8; odds ratio = 2.09, 95% confidence interval = 1.59 to 2.76). While searching for a replication cohort, the same genetic determinant was established through a genome-wide association study of NSCL/P in Germany, so this previous report acts as a de novo replication for our independent observation outlined here.

Conclusions

These results strongly suggest that a locus on 8q24 is involved in the pathogenesis of NSCL/P.

Section snippets

Methods

All cases and control subjects were consecutively recruited within the same study from the Greater Philadelphia area from 2006 to 2009 at the Children's Hospital of Philadelphia. All of these participants had blood 8 mL drawn in an ethylenediamine tetraacetic acid collection tube, and DNA was subsequently extracted for genotyping. All subjects were biologically unrelated, that is, simplex cases, and were aged between 0 and 18 years of age. Of the 111 NSCL/P cases, 77 were male and 34 were

Results

After genotyping on our study cohort of 111 NSCL/P cases and 5951 control subjects of European ancestry, the resulting genomic inflation factor was only 1.025, suggesting that the ancestry of cases and control subjects is well matched. SNPs were rejected with call rates <95%, minor allele frequencies <1% and with hardy Weinberg equilibrium P < 10−5, leaving 495 858 SNPs available for analysis. Single-marker allele frequencies were compared by use of χ2 statistics for all markers (Figure).

One

Discussion

Molecular events that strongly influence the formation of orofacial structures have been shown to be tightly controlled by sets of genes including fibroblast growth factors, sonic hedgehog, bone morphogenetic proteins, members of the transforming growth factor β super-family and transcription factors.5 Although such knowledge has significantly enhanced our current understanding of the molecular events underlying orofacial clefting, NSCL/P is considered a classic example of a complex trait

References (29)

  • Stanier P, Moore GE. Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic...
  • L.E. Mitchell et al.

    Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis

    Am J Hum Genet

    (1992)
  • P.A. Mossey et al.

    Epidemiology of oral clefts: An international perspective

  • A.P. Vanderas

    Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review

    Cleft Palate J

    (1987)
  • Cited by (224)

    • Gene × environment associations in orofacial clefting

      2023, Current Topics in Developmental Biology
      Citation Excerpt :

      On the other hand, genome-wide association studies (GWAS) of millions of variants across the genome have cumulatively identified more than 50 associated genes/regions achieving a strict p-value threshold for genome-wide statistical significance (see reviews (Beaty, Marazita, & Leslie, 2016; Moreno Uribe & Marazita, 2021)). These genes/regions have been identified across multiple independent GWASs for CL/P (Beaty et al., 2010; Birnbaum et al., 2009; Camargo et al., 2012; Gowans et al., 2016; Grant et al., 2009; Leslie, Carlson, et al., 2016; Mangold et al., 2010; Sun et al., 2015); and CP (Beaty et al., 2011; Butali et al., 2019; Leslie, Liu, et al., 2016)), and meta-analyses combining the separate studies (Carlson et al., 2019; Leslie, Carlson, Shaffer, Butali, et al., 2017, Leslie, Carlson, Shaffer, Buxo, et al., 2017; Ludwig et al., 2012). Cumulatively, these ∼50 genes/regions explain about 20–25% of the heritability of nonsyndromic OFCs (Morris et al., 2020; Saleem, Zaib, Sun, & Fu, 2019).

    • Pathway analysis identified a significant association between cell-cell adherens junctions-related genes and non-syndromic cleft lip/palate in 895 Asian case-parent trios

      2022, Archives of Oral Biology
      Citation Excerpt :

      This study provided additional evidence for this group of AJs-related genes that they may be involved in the aetiology of NSCL/P (Bishop et al., 2020). However, none of the abovementioned six cell-cell AJs-related genes identified in sequencing studies were observed to yield genome-wide significant evidence of association in any of the 10 independent genome-wide association studies (Beaty et al., 2010; Birnbaum et al., 2009; Butali et al., 2019; Grant et al., 2009; Leslie et al., 2016; Mangold et al., 2010; Mukhopadhyay et al., 2021; Sun et al., 2015; van Rooij et al., 2019; Yu et al., 2017). To explain this inconsistency, we conducted an analysis of the association between these six genes along with ESRP1, a gene that functions in the same way as ESRP2 in mice models (Warzecha, Shen, Xing, & Carstens, 2009), and NSCL/P in the current study.

    View all citing articles on Scopus

    This research was financially supported by the Children's Hospital of Philadelphia and in part by a Research Development Award from the Cotswold Foundation (H.H. & S.F.A.G). The authors declare no conflicts of interest.

    View full text