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. 2012 May;76(3):221-36.
doi: 10.1111/j.1469-1809.2012.00707.x.

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts

Oivind Skare  1 , Astanand Jugessur, Rolv Terje Lie, Allen James Wilcox, Jeffrey Clark Murray, Astrid Lunde, Truc Trung Nguyen, Håkon Kristian Gjessing
Affiliations

Application of a novel hybrid study design to explore gene-environment interactions in orofacial clefts

Oivind Skare et al. Ann Hum Genet. 2012 May.

Abstract

Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.

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Figures

Figure 1
Figure 1
Analysis of GxE interaction for isolated cleft palate only (CPO). The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are indicated by the grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
Figure 2
Figure 2
Analysis of GxE interaction for isolated cleft lip only (CLO). The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are indicated by the grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
Figure 3
Figure 3
Analysis of GxE interaction for isolated cleft lip with or without cleft palate (CL/P). The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are indicated by the grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
Figure 4
Figure 4
Analysis of GxE interaction for isolated cleft palate only (CPO). The plots show sorted q-values from the false discovery rate (FDR) analysis for each maternal first-trimester exposure. Points falling below the q=0.05 line in the plots would indicate statistical significance.
Figure 5
Figure 5
Analysis of GxE interaction for isolated cleft lip only (CLO). The plots show sorted q-values from the false discovery rate (FDR) analysis for each maternal first-trimester exposure. Points falling below the q=0.05 line in the plots would indicate statistical significance.
Figure 6
Figure 6
Analysis of GxE interaction for isolated cleft lip with or without cleft palate (CL/P). The plots show sorted q-values from the false discovery rate (FDR) analysis for each maternal first-trimester exposure. Points falling below the q=0.05 line in the plots would indicate statistical significance.
Figure 7
Figure 7
Analysis of 21 folate-pathway genes for isolated cleft lip with or without cleft palate (CL/P). The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are indicated by the grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
Figure 8
Figure 8
Analysis of 28 detoxification-pathway genes for isolated cleft lip with or without cleft palate (CL/P). The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are indicated by the grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
Figure 9
Figure 9
Simulated data under the null hypothesis of no GxE interaction effects. The QQ-plots compare p-values (−log10 scale) with an expected uniform distribution under the null (sloping line). The pointwise 95% confidence bounds for the p-values are shown as grey shadings around the expected p-values. The dotted lines correspond to a p-value of 0.05.
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