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Human Molecular Genetics Advance Access originally published online on February 13, 2006
Human Molecular Genetics 2006 15(6):807-819; doi:10.1093/hmg/ddl024
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© The Author 2006. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

Association between two µ-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence

Huiping Zhang1,2, Xingguang Luo1,2, Henry R. Kranzler3, Jaakko Lappalainen1,2, Bao-Zhu Yang1,2, Evgeny Krupitsky4, Edwin Zvartau4 and Joel Gelernter1,2,*

1Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA, 2VA Connecticut Healthcare System, Psychiatry 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA, 3Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA and 4St Petersburg State Pavlov Medical University, St Petersburg, Russia

* To whom correspondence should be addressed. Tel: +1 2039325711 ext. 3599; Fax: +1 2039373897; Email: joel.gelernter{at}yale.edu

Received November 7, 2005; Accepted December 22, 2005

We examined 13 single nucleotide polymorphisms (SNPs) spanning the coding region of the µ-opioid receptor gene (OPRM1), among 382 European Americans (EAs) affected with substance dependence [alcohol dependence (AD) and/or drug dependence (DD)] and 338 EA healthy controls. These SNPs delineated two haplotype blocks. Genotype distributions for all SNPs were in Hardy–Weinberg equilibrium (HWE) in controls, but in cases, four SNPs in Block I and three SNPs in Block II showed deviation from HWE. Significant differences were found between cases and controls in allele and/or genotype frequencies for six SNPs in Block I and two SNPs in Block II. Association of SNP4 in Block I with DD (allele: P=0.004), SNP5 in Block I with AD and DD (allele: P≤0.005 for both) and two SNPs in Block II with AD (SNP11 genotype: P=0.002; SNP12 genotype: P=0.001) were significant after correction for multiple testing. Frequency distributions of haplotypes (constructed by five tag SNPs) differed significantly for cases and controls (P<0.001 for both AD and DD). Logistic regression analyses confirmed the association between OPRM1 variants and substance dependence, when sex and age of subjects and alleles, genotypes, haplotypes or diplotypes of five tag SNPs were considered. Population structure analyses excluded population stratification artifact. Additional supporting evidence for association between OPRM1 and AD was obtained in a smaller Russian sample (247 cases and 100 controls). These findings suggest that OPRM1 intronic variants play a role in susceptibility to AD and DD in populations of European ancestry.


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