Human Molecular Genetics Advance Access originally published online on August 17, 2009
Human Molecular Genetics 2009 18(22):4457-4466; doi:10.1093/hmg/ddp388
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A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women
1 Department of Social Medicine, University of Bristol, Bristol BS8 2PS, UK, 2 MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol BS8 2BN, UK, 3 National Perinatal Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK and 4 Section of Developmental Psychiatry, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
* To whom correspondence should be addressed at: Department of Social Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK. Tel: +44 1179287296; Fax: +44 1179287325; Email: l.zuccolo{at}bristol.ac.uk
Received June 26, 2009; Accepted August 12, 2009
Pregnant women are advised to abstain from alcohol despite insufficient evidence on the fetal consequences of moderate prenatal alcohol use. Mendelian randomization could help distinguish causal effects from artifacts due to residual confounding and measurement errors; however, polymorphisms reliably associated with alcohol phenotypes are needed. We aimed to test whether alcohol dehydrogenase (ADH) gene variants were associated with alcohol use before and during pregnancy. Ten variants in four ADH genes were genotyped in women from South-West England. Phenotypes of interest were quantity and patterns of alcohol consumption before and during pregnancy, including quitting alcohol following pregnancy recognition. We tested single-locus associations between genotypes and phenotypes with regression models. We used Bayesian models (multi-locus) to take account of linkage disequilibrium and reanalyzed the data with further exclusions following two conservative definitions of ‘white ethnicity’ based on the woman's reported parental ethnicity or a set of ancestry-informative genetic markers. Single-locus analyses on 7410 women of white/European background showed strong associations for rs1229984 (ADH1B). Rare allele carriers consumed less alcohol before pregnancy [odds ratio (OR) = 0.69; 95% confidence interval (CI): 0.56–0.86, P = 0.001], were less likely to have ‘binged’ during pregnancy (OR = 0.55, 95% CI: 0.38–0.78, P = 0.0009), and more likely to have abstained in the first trimester of gestation (adjusted OR = 1.42, 95% CI: 1.12–1.80, P = 0.004). Multi-locus models confirmed these results. Sensitivity analyses did not suggest the presence of residual population stratification. We confirmed the established association of rs1229984 with reduced alcohol consumption over the life-course, contributing new evidence of an effect before and during pregnancy.