Genotype patterns that contribute to increased risk for or protection from developing heroin addiction.
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 mu 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.
Nielsen
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Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10065, USA. nielsen@rockefeller.edu
Ji
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Yuferov
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V
Ho
A
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Chen
A
A
Levran
O
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Ott
J
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Kreek
M J
MJ
D041321:Chromosomes, Human, X; D056931:Cryptochromes; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005420:Flavoproteins / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006556:Heroin Dependence; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D044465:White People; D000099251:Myocardin
D056931:Cryptochromes; D004268:DNA-Binding Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018094:Receptors, Metabotropic Glutamate; D017450:Receptors, Opioid, mu; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C539882:NR4A2 protein, human; C485764:OPRM1 protein, human; C113897:metabotropic glutamate receptor 6; C111435:metabotropic glutamate receptor 8