Assessing the impact of nicotine dependence genes on the risk of facial clefts: An example of the use of national registry and biobank data
AbstractBackground: Maternal smoking during pregnancy has consistently been associated with risk of facial clefts in offspring, although these studies cannot establish causation. The association between maternal smoking and clefting risk may be caused by genes that influence nicotine dependence and other risk behaviors. Gamma-aminobutyric acid B receptor 2 (GABBR2), dopa decarboxylase (DDC), and cholinergic receptor nicotinic alpha 4 (CHRNA4) are three examples of genes that have previously shown strong associations with nicotine dependence. Methods: We used a population-based sample of 377 case-parent triads of cleft lip with or without cleft palate (CL/P) and 762 control-parent triads from Norway (1996-2001) to investigate whether variants in GABBR2, DDC and CHRNA4 are associated with maternal first-trimester smoking and with clefting risk. We used HAPLIN (Gjessing et al. 2006), a statistical software tailored for family-based association tests, to perform haplotype-based analyses of 12 SNPs in these genes (rs10985765, rs1435252, rs3780422, rs2779562, and rs3750344 in GABBR2; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 in DDC; rs4522666 and rs1044393 in CHRNA4). Results: When analyzed one at a time, there was little evidence of association between any of the 12 SNPs and maternal first-trimester smoking. In haplotype analyses, however, one copy of the maternal G-G-c-G-c haplotype in DDC (SNP order as above) was linked with smoking prevalence (odds ratio=1.5; 5% confidence interval: 1.0-2.1). This same haplotype also increased the risk of isolated CL/P in offspring by 1.5-fold with one copy and 2.4-fold with two copies (Ptrend=0.06). No statistically significant associations were detected with GABBR2 and CHRNA4. Conclusions: Despite strong associations previously reported between nicotine dependence and variants in GABBR2, DDC and CHRNA4, these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of the DDC haplotype with CL/P suggests that this haplotype may either have direct effects on clefts or it may influence clefting risks through other yet unexplored risk behavior(s).
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