title: Assessing the impact of nicotine dependence genes on the risk of facial clefts: An example of the use of national registry and biobank data.
abstract: BACKGROUND
  Maternal smoking during pregnancy has been associated with risk of facial clefts in offspring, but causation has not yet been established. It is possible that the effect of maternal smoking on facial clefts is mediated through genes that are involved in nicotine dependence. 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 trios of cleft lip with or without cleft palate (CL/P) and 762 control-parent trios from Norway (1996-2001) to investigate whether variants inGABBR2, DDCandCHRNA4are 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 on 12 SNPs in these genes (rs10985765, rs1435252, rs3780422, rs2779562, and rs3750344 inGABBR2; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 inDDC; rs4522666 and rs1044393 inCHRNA4).
  
  
  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 inDDCwas linked with smoking prevalence (odds ratio: 1.5; 95% 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 withGABBR2andCHRNA4.
  
  
  CONCLUSIONS
  Despite strong associations previously reported between nicotine dependence and variants inGABBR2,DDCandCHRNA4, these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of theDDChaplotype 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).
authors.affiliation: Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway ; Craniofacial Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Astanand
authors.initials: A
authors.lastname: Jugessur
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, Durham, North Carolina, USA.
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Wilcox
authors.affiliation: Departments of Pediatrics, Epidemiology and Biological Sciences, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway ; Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway.
authors.forename: Håkon K
authors.initials: HK
authors.lastname: Gjessing
authors.affiliation: Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.
authors.forename: Truc Trung
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Nilsen
authors.affiliation: Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway ; Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.
authors.forename: Rolv T
authors.initials: RT
authors.lastname: Lie
keywords: Cleft lip; cleft palate; nicotine dependence; smoking