Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

Abstract

A genome-wide association study was conducted using microarray technology to identify genes that may be associated with the vulnerability to develop heroin addiction, using DNA from 104 individual former severe heroin addicts (meeting Federal criteria for methadone maintenance) and 101 individual control subjects, all Caucasian. Using separate analyses for autosomal and X chromosomal variants, we found that the strongest associations of allele frequency with heroin addiction were with the autosomal variants rs965972, located in the Unigene cluster Hs.147755 (experiment-wise q=0.053), and rs1986513 (q=0.187). The three variants exhibiting the strongest association with heroin addiction by genotype frequency were rs1714984, located in an intron of the gene for the transcription factor myocardin (P=0.000022), rs965972 (P=0.000080) and rs1867898 (P=0.000284). One genotype pattern (AG-TT-GG) was found to be significantly associated with developing heroin addiction (odds ratio (OR)=6.25) and explained 27% of the population attributable risk for heroin addiction in this cohort. Another genotype pattern (GG-CT-GG) of these variants was found to be significantly associated with protection from developing heroin addiction (OR=0.13), and lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. Evidence was found for involvement of five genes in heroin addiction, the genes coding for the μ opioid receptor, the metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 and cryptochrome 1 (photolyase-like). This approach has identified several new genes potentially associated with heroin addiction and has confirmed the role of OPRM1 in this disease.

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Acknowledgements

We thank Dorothy Melia, RN, Kathy Bell, RN, Elizabeth Ducat, NP, Lisa Borg, MD, Pauline McHugh, MD, James Schluger, MD, and Heather Hofflich, DO for recruiting, screening and assessment of study subjects and Connie Zhao, PhD for the processing of the microarrays. We thank Oscar Lao, PhD, Erasmus University Medical Centre Rotterdam, The Netherlands, for assistance with the analysis of population structure and for providing the genotypes of the CEPH-HGDP subjects. We also thank the late K Steven LaForge, PhD, for his role in the planning of these genetic studies. This work was supported in part by NIH-NIDA P60-05130 (MJK), NIH-NIDA K05-00049 (MJK), NIH-RR UL1RR024143 (BC), NIH-MH R01-44292 (JO) and NSFC grant 30730057 from the Chinese Government (JO).

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Correspondence to D A Nielsen.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Nielsen, D., Ji, F., Yuferov, V. et al. Genotype patterns that contribute to increased risk for or protection from developing heroin addiction. Mol Psychiatry 13, 417–428 (2008) doi:10.1038/sj.mp.4002147

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Keywords

  • addiction
  • gene
  • heroin
  • microarray
  • polymorphism

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