Beaty TH, Murray JC, Marazita ML et al.A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42:525-529

Johns Hopkins University, School of Public Health, Baltimore, Maryland, USA.
Nature Genetics (Impact Factor: 29.35). 06/2010; 42(6):525-9. DOI: 10.1038/ng.580
Source: PubMed


Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

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Available from: Terri Beaty
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    • "we observed nominal significance that could be considered evidence of replication . That we didn't observe stronger association for these variants might be due to inadequate power of our sample sizes or failure of some SNPs to associate with clefting in some ancestral groups as we have previously noted between Asian and European populations [Beaty et al., 2010] "
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    ABSTRACT: Genome wide association (GWA) studies have successfully identified at least a dozen loci associated with orofacial clefts. However, these signals may be unique to specific populations and require replication to validate and extend findings as a prelude to etiologic SNP discovery. We attempted to replicate the findings of a recent meta-analysis of orofacial cleft GWA studies using four different ancestral populations. We studied 946 pedigrees (3,436 persons) of European (US white and Danish) and Asian (Japanese and Mongolian) origin. We genotyped six SNPs that represented the most significant P-value associations identified in published studies: rs742071 (1p36), rs7590268 (2p21), rs7632427 (3p11.1), rs12543318 (8q21.3), rs8001641 (13q31.1), and rs7179658 (15q22.2). We directly sequenced three non-coding conserved regions 200 kb downstream of SPRY2 in 713 cases, 438 controls, and 485 trios from the US, Mongolia, and the Philippines. We found rs8001641 to be significantly associated with nonsyndromic cleft lip with cleft palate (NSCLP) in Europeans (P-value = 4 × 10(-5) , ORtransmission = 1.86 with 95% confidence interval: 1.38-2.52). We also found several novel sequence variants in the conserved regions in Asian and European samples, which may help to localize common variants contributing directly to the risk for NSCLP. This study confirms the prior association between rs8001641 and NSCLP in European populations. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2015 · American Journal of Medical Genetics Part A
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    • "Although it makes sense that syndromic cases can be more easily collated into homogeneous study cohorts and it is clear that NSCL/P is therefore more heterogeneous, the lack of success has still been something of a surprise on a number of levels. First, NSCL/P cases are more common and much effort has gone into the study of large cohorts of these patients including GWAS [Beaty et al., 2010; Ludwig et al., 2012; Böhmer et al., 2013; Ludwig et al., 2014]. Secondly, there is no shortage of families with a history of clefts, including many multiplex, multi-generation families (showing clear inheritance, albeit often without full penetrance), which have been subject to linkage techniques and recently whole exome sequencing strategies [Dixon et al., 2011; Ng et al., 2010a, 2010b; Mitchell et al., 2012]. "
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    ABSTRACT: Cleft lip and/or cleft palate (CL/P) collectively are well known as being amongst the most common birth defects but we still have difficulty explaining why the majority of cases occur. In general, sporadic cases with no family history may be more related to environmental risks, while the presence of one or more affected relative in the same family strongly suggests that genetic factors are the main contributor. Orofacial clefts can occur in conjunction with other defects (syndromic CL/P) or as an isolated defect (non-syndromic - NSCL/P). CL/P syndromes have been studied intensively and appear to have a stronger genetic aetiology. Here we report on the relationship between syndromic and NSCL/P as a phenotypic spectrum resulting from coding or non-coding mutations respectively. We review certain abnormalities that are most frequently associated with CL/P, including dental, heart, brain, skin and certain types of cancer and examine some of the genes that are involved. We include the outcome of recent NSCL/P GWAS data and we will discuss how the genes at these loci might contribute towards clarifying the genetics of CL/P.
    Full-text · Article · Apr 2014 · European journal of medical genetics
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    • "Selective* references reporting association with NSCL/P Gene expression pattern and/or craniofacial anomalies associated References PAX7 Sull et al. (2009) and Ludwig et al. (2012) PAX 7 is expressed in craniofacial neural crest derivatives and knockout mice exhibit malformations in the maxilla and nose Mansouri et al. (1996) ABCA4-ARHGAP29 Beaty et al. (2010) and Leslie et al. (2012) ARHGAP29 is expressed in the medial and lateral nasal processes, maxilla, mandible and secondary palatal shelves Leslie et al. (2012) IRF6 Rahimov et al. (2008) IRF6 knockouts present with shorter and rounded snouts and jaws Ingraham et al. (2006) MSX1 Lidral et al. (1998) MSX1 null mice present with anomalies of the frontal and nasal bone, reduced overall length of the mandible, deficient alveolar bone, abnormal dental development and cleft palate Satokata & Maas (1994) 8q24_rs987525 Birnbaum et al. (2009) and Grant et al. (2009) rs987525 was found associated with bizygomatic distance in a recent GWAS study Boehringer et al. (2011) FOXE1 Moreno et al. (2009) Mutations in FOXE caused Bamforth–Lazarous syndrome in humans characterized by hypothyroidism, hair and craniofacial anomalies including cleft palate and ocular hypertelorism Bamforth et al. (1989) TGFB3 Lidral et al. (1998) TGFB3 Null mice present with cleft palate. TGFB3 is differentially expressed in the different species of bird beaks and presumably playing a role in the morphogenesis of avian beaks Kaartinen et al. (1995) and Brugmann et al. (2010) MAFB Beaty et al. (2010) MAFB is expressed in the craniofacial ectoderm, palatal shelves and nasal septum Beaty et al. (2010) *Many other studies have reported association between these genes and NSCL/P (see review Dixon et al., 2011; Marazita, 2012). Table 2 Listing and description of left–right (L/R) body patterning candidate genes genotyped for the present study. "
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    ABSTRACT: Family relatives of children with nonsyndromic cleft lip with or without cleft palate (NSCL/P) who presumably carry a genetic risk yet do not manifest overt oral clefts, often present with distinct facial morphology of unknown genetic etiology. This study investigates distinct facial morphology among unaffected relatives and examines whether candidate genes previously associated with overt NSCL/P and left–right body patterning are correlated with such facial morphology. Cases were unaffected relatives of individuals with NSCL/P (n = 188) and controls (n = 194) were individuals without family history of NSCL/P. Cases and controls were genotyped for 20 SNPs across 13 candidate genes for NSCL/P (PAX7, ABCA4-ARHGAP29, IRF6, MSX1, PITX2, 8q24, FOXE1, TGFB3 and MAFB) and left–right body patterning (LEFTY1, LEFTY2, ISL1 and SNAI1). Facial shape and asymmetry phenotypes were obtained via principal component analyses and Procrustes analysis of variance from 32 coordinate landmarks, digitized on 3D facial images. Case–control comparisons of phenotypes obtained were performed via multivariate regression adjusting for age and gender. Phenotypes that differed significantly (P < 0.05) between cases and controls were regressed on the SNPs one at a time. Cases had significantly (P < 0.05) more profile concavity with upper face retrusion, upturned noses with obtuse nasolabial angles, more protrusive chins, increased lower facial heights, thinner and more retrusive lips and more protrusive foreheads. Furthermore, cases showed significantly more directional asymmetry compared to controls. Several of these phenotypes were significantly associated with genetic variants (P < 0.05). Facial height and width were associated with SNAI1. Midface antero-posterior (AP) projection was associated with LEFTY1. The AP position of the chin was related to SNAI1, IRF6, MSX1 and MAFB. The AP position of the forehead and the width of the mouth were associated with ABCA4–ARHGAP29 and MAFB. Lastly, facial asymmetry was related to LEFTY1, LEFTY2 and SNAI1. This study demonstrates that, genes underlying lip and palate formation and left–right patterning also contribute to facial features characteristic of the NSCL/P spectrum.
    Full-text · Article · Apr 2014 · Journal of Anatomy
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