Abstract
BackgroundFacial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads).Methodology/Principal FindingsWe used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM.Conclusion/SignificanceStrong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting—with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field.
Highlights
With an average worldwide prevalence of 1.2/1000 live births, facial clefts are the most common craniofacial birth defects and one of the most common major types of defect in humans [1]
Linkage studies have been successful in mapping a number of these key candidate genes [8], studies relying on linkage disequilibrium (LD) have grown in popularity because they can be more effective in detecting weaker associations from multiple common and lowpenetrance alleles [13,14]
Of the 334 autosomal cleft candidate genes analyzed in this study, associations with seven genes—interferon regulatory factor 6 (IRF6), platelet-derived growth factor C (PDGFC), alcohol dehydrogenase 1C (ADH1C), mohawk homeobox (MKX), ALX3, Figure 1
Summary
With an average worldwide prevalence of 1.2/1000 live births, facial clefts are the most common craniofacial birth defects and one of the most common major types of defect in humans [1]. Linkage studies have been successful in mapping a number of these key candidate genes [8], studies relying on linkage disequilibrium (LD) have grown in popularity because they can be more effective in detecting weaker associations from multiple common and lowpenetrance alleles [13,14]. Analyses based on haplotypes can outperform single-point analyses in which multiple SNPs in a gene are interrogated one at a time, because haplotypes can increase the overall information content at a given locus [15] and potentially capture association signals from variants that have not been directly typed [16]. Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads)
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