title: H2 haplotype at chromosome 17q21.31 protects against childhood sexual abuse-associated risk for alcohol consumption and dependence.
abstract: Animal research supports a central role for corticotropin-releasing factor (CRF) in actions of ethanol on brain function. An examination of alcohol consumption in adolescents reported a significant genotype x environment (G x E) interaction involving rs1876831, a corticotropin-releasing hormone receptor 1 (CRHR1) polymorphism, and negative events. CRHR1 and at least four other genes are located at 17q21.31 in an extremely large block of high linkage disequilibrium resulting from a local chromosomal inversion; the minor allele of rs1876831 is contained within the H2 haplotype. Here, we examine whether G x E interactions involving this haplotype and childhood sexual abuse (CSA) are associated with risk for alcohol consumption and dependence in Australian participants (n = 1128 respondents from 476 families) of the Nicotine Addiction Genetics project. Telephone interviews provided data on DSM-IV alcohol dependence diagnosis and CSA and enabled calculation of lifetime alcohol consumption factor score (ACFS) from four indices of alcohol consumption. Individuals reporting a history of CSA had significantly higher ACFS and increased risk for alcohol dependence. A significant G x E interaction was found for ACFS involving the H2 haplotype and CSA (P < 0.017). A similar G x E interaction was associated with protective effects against alcohol dependence risk (odds ratio 0.42; 95% confidence interval 0.20-0.89). For each outcome, no significant CSA-associated risk was observed in H2 haplotype carriers. These findings support conducting further investigation of the H2 haplotype to determine the gene(s) responsible. Our results also suggest that severe early trauma may prove to be an important clinical covariate in the treatment of alcohol dependence.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, USA.
authors.forename: Elliot C
authors.initials: EC
authors.lastname: Nelson
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Jen C
authors.initials: JC
authors.lastname: Wang
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
authors.forename: F Scott
authors.initials: FS
authors.lastname: Saccone
authors.forename: Jason
authors.initials: J
authors.lastname: Kern
authors.forename: Julia D
authors.initials: JD
authors.lastname: Grant
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schrage
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
mesh_terms: D000293:Adolescent; D000328:Adult; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D000483:Alleles; D002648:Child; D002650:Child Abuse, Sexual / Q000523:psychology* / Q000706:statistics & numerical data; D007446:Chromosome Inversion / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D015331:Cohort Studies; D015897:Comorbidity; D004200:Diseases in Twins / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics* / Q000523:psychology; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008016:Life Change Events; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology / Q000235:genetics / Q000523:psychology; D012931:Social Environment; D044465:White People / Q000235:genetics; D000099052:CRF Receptor, Type 1
chemical_list: D000949:Histocompatibility Antigens Class II; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1