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Human Molecular Genetics Advance Access published online on February 13, 2006
Human Molecular Genetics, 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@oupjournals.org
Received November 7, 2005
Revised December 20, 2005
Accepted February 9, 2006

Article

Association between Two µ Opioid Receptor Gene (OPRM1) Haplotype Blocks and Drug or Alcohol Dependence

Huiping Zhang 1, Xingguang Luo 1, Henry R. Kranzler 2, Jaakko Lappalainen 1, Bao-Zhu Yang 1, Evgeny Krupitsky 3, Edwin Zvartau 3, and Joel Gelernter 4 *

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

* To whom correspondence should be addressed.
Joel Gelernter, E-mail: joel.gelernter{at}yale.edu


  Abstract

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; SNP 12 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 alcohol and drug dependence in populations of European ancestry.


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