title: A non-synonymous variant in ADH1B is strongly associated with prenatal alcohol use in a European sample of pregnant women.
abstract: 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.
authors.affiliation: Department of Social Medicine, University of Bristol, Bristol, UK. l.zuccolo@bristol.ac.uk
authors.forename: Luisa
authors.initials: L
authors.lastname: Zuccolo
authors.forename: Nicola
authors.initials: N
authors.lastname: Fitz-Simon
authors.forename: Ron
authors.initials: R
authors.lastname: Gray
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: Kapil
authors.initials: K
authors.lastname: Sayal
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000428:Alcohol Drinking / Q000235:genetics*; D004739:England; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C489332:ADH1B protein, human; D000426:Alcohol Dehydrogenase
references.citation: Annu Rev Genet. 2003;37:197-219
references.pmid: 14616060
references.citation: Genet Epidemiol. 2006 Apr;30(3):231-47
references.pmid: 16544290
references.citation: Lancet. 1973 Nov 3;302(7836):999-1001
references.pmid: 4127281
references.citation: Alcohol Clin Exp Res. 2008 May;32(5):785-95
references.pmid: 18331377
references.citation: Br J Cancer. 2005 Jun 6;92(11):2039-41
references.pmid: 15886702
references.citation: Arch Gen Psychiatry. 2007 Nov;64(11):1296-304
references.pmid: 17984398
references.citation: Alcohol Alcohol. 1994 Nov;29(6):707-10
references.pmid: 7695788
references.citation: Alcohol. 2003 Apr;29(3):131-5
references.pmid: 12798968
references.citation: Neurosci Biobehav Rev. 2007;31(2):221-9
references.pmid: 16908065
references.citation: BMJ. 2005 May 7;330(7499):1076-9
references.pmid: 15879400
references.citation: Am J Clin Nutr. 2005 May;81(5):1005-11
references.pmid: 15883422
references.citation: Alcohol Clin Exp Res. 2004 Jan;28(1):10-4
references.pmid: 14745297
references.citation: Eur J Public Health. 2007 Aug;17(4):394-9
references.pmid: 17158790
references.citation: BMC Genet. 2005 Dec 30;6 Suppl 1:S124
references.pmid: 16451582
references.citation: BMC Public Health. 2009 Jun 05;9:175
references.pmid: 19500375
references.citation: Science. 2007 Aug 24;317(5841):1036; author reply 1036
references.pmid: 17717170
references.citation: Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):245-56
references.pmid: 18226080
references.citation: Int J Cancer. 2007 Nov 1;121(9):2060-4
references.pmid: 17631643
references.citation: Alcohol Clin Exp Res. 1998 Oct;22(7):1463-9
references.pmid: 9802529
references.citation: Pediatrics. 2007 Feb;119(2):e426-34
references.pmid: 17272604
references.citation: Hum Mol Genet. 2009 Apr 15;18(8):1533-42
references.pmid: 19193628
references.citation: Hum Mol Genet. 2006 May 1;15(9):1539-49
references.pmid: 16571603
references.citation: Biochemistry. 1984 Nov 20;23(24):5847-53
references.pmid: 6395883
references.citation: Pharmacogenomics J. 2008 Jun;8(3):220-7
references.pmid: 17923853
references.citation: Am J Hum Genet. 2006 Jun;78(6):973-87
references.pmid: 16685648
references.citation: Int J Epidemiol. 1988 Dec;17(4):950-4
references.pmid: 3225111
references.citation: Hepatology. 2006 Feb;43(2):352-61
references.pmid: 16440362
references.citation: Pediatrics. 2008 Dec;122(6):e1225-30
references.pmid: 19047223
references.citation: Addiction. 2003 Nov;98(11):1513-20
references.pmid: 14616177
references.citation: Am J Med Genet. 1998 May 8;81(3):207-15
references.pmid: 9603606
references.citation: Hum Mol Genet. 2009 Feb 1;18(3):580-93
references.pmid: 18996923
references.citation: Pediatrics. 2009 Feb;123(2):e289-96
references.pmid: 19171582
references.citation: Neurotoxicol Teratol. 2005 May-Jun;27(3):395-406
references.pmid: 15939200
references.citation: Am J Obstet Gynecol. 2007 Jul;197(1):12-25
references.pmid: 17618743
references.citation: J Abnorm Psychol. 2005 Aug;114(3):456-65
references.pmid: 16117582
references.citation: Twin Res Hum Genet. 2008 Jun;11(3):287-305
references.pmid: 18498207
references.citation: Behav Genet. 2005 Sep;35(5):509-24
references.pmid: 16184481
references.citation: PLoS Med. 2008 Mar 4;5(3):e52
references.pmid: 18318597
references.citation: Int J Cancer. 2007 Sep 1;121(5):1047-54
references.pmid: 17471563
references.citation: Am J Epidemiol. 1991 Apr 15;133(8):810-7
references.pmid: 2021148
references.citation: Eur J Hum Genet. 2000 Sep;8(9):653-60
references.pmid: 10980570
references.citation: Alcohol Clin Exp Res. 2006 Sep;30(9):1470-8
references.pmid: 16930209
references.citation: Psychol Bull. 2006 Jul;132(4):607-21
references.pmid: 16822169
references.citation: Hum Mol Genet. 2009 Aug 1;18(15):2922-7
references.pmid: 19429911
references.citation: Am J Hum Genet. 2009 Jan;84(1):89-92; author reply 92-4
references.pmid: 19124091
references.citation: Am J Epidemiol. 1999 Jul 1;150(1):105-12
references.pmid: 10400547
references.citation: Hepatology. 2000 Apr;31(4):984-9
references.pmid: 10733556
references.citation: Nat Genet. 2008 Jun;40(6):707-9
references.pmid: 18500343
references.citation: Am J Epidemiol. 1999 Feb 1;149(3):290
references.pmid: 9927226
references.citation: Ann Hum Genet. 2004 Mar;68(Pt 2):93-109
references.pmid: 15008789
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):248-54
references.pmid: 19124505
references.citation: Am J Obstet Gynecol. 2008 Apr;198(4):407.e1-5
references.pmid: 18221928
references.citation: J Epidemiol Community Health. 2007 Dec;61(12):1069-73
references.pmid: 18000129
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Alcohol Clin Exp Res. 2009 May;33(5):848-57
references.pmid: 19298322
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: Paediatr Perinat Epidemiol. 2001 Jan;15(1):74-87
references.pmid: 11237119
references.citation: Neuropsychopharmacology. 2006 May;31(5):1085-95
references.pmid: 16237392
references.citation: Alcohol Clin Exp Res. 2008 May;32(5):868-73
references.pmid: 18373726
references.citation: Addiction. 2001 Aug;96(8):1199-209
references.pmid: 11487425
references.citation: PLoS Med. 2007 Dec;4(12):e352
references.pmid: 18076282
references.citation: Addiction. 2009 Aug;104(8):1270-3
references.pmid: 19215606
references.citation: Ann Med. 2008;40(7):524-41
references.pmid: 18608114
references.citation: Am J Med Genet. 2000 Oct 9;96(5):632-7
references.pmid: 11054770
references.citation: Am J Epidemiol. 2009 Jan 1;169(1):54-66
references.pmid: 18936436
references.citation: BMJ. 2005 Feb 19;330(7488):375-6
references.pmid: 15718517
references.citation: Am J Hum Genet. 2007 Oct;81(4):842-6
references.pmid: 17847010
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1301-5
references.pmid: 18454434