Abstract
BackgroundOrofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers.Methodology/Principal FindingsWe added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample.ConclusionsThe association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.
Highlights
Orofacial clefts are relatively common craniofacial birth defects, with a birth prevalence of about 1–2/1000
The association of OFD1 with iCL/P is plausible given the biological relevance of this gene
First-degree relatives of an affected individual have a 30–40 fold higher recurrence risk compared with the background population [5,6], and heritability estimates were recently reported to be as high as 91% for CL/P and 90% for CP in a large Danish twin study [7]
Summary
Orofacial clefts are relatively common craniofacial birth defects, with a birth prevalence of about 1–2/1000. They require extensive surgical, nutritional, dental, speech, behavioral and medical interventions, and impose a substantial economic and personal health burden [1,2]. Clefts are characterized by a strong genetic component, as evidenced by studies of familial recurrence risk and heritability [4]. The strong genetic component to clefting has spurred decadelong efforts to identify the genes underpinning these complex birth defects. The first genome-wide association study (GWAS) identified a strong signal on chromosome 8q24 in individuals of central European ancestry. This association was subsequently replicated in three. Genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers
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