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 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1


  1. 1

    Kreek MJ . Gene diversity in the endorphin system: SNPs, chips, and possible implications. In: Yudell M, DaSalle R (eds). The Genomic Revolution: Unveiling the Unity of Life. Joseph Henry Press: Washington, DC, 2002, pp 97–108.

  2. 2

    Kendler KS, Jacobson KC, Prescott CA, Neale MC . Specificity of genetic and environmental risk factors for use and abuse/dependence of cannabis, cocaine, hallucinogens, sedatives, stimulants, and opiates in male twins. Am J Psychiatry 2003; 160: 687–695.

  3. 3

    Tsuang MT, Lyons MJ, Meyer JM, Doyle T, Eisen SA, Goldberg J et al. Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch Gen Psychiatry 1998; 55: 967–972.

  4. 4

    Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N et al. Genetic influences on DSM-III-R drug abuse and dependence: a study of 3372 twin pairs. Am J Med Genet 1996; 67: 473–477.

  5. 5

    LaForge KS, Yuferov V, Kreek MJ . Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol 2000; 410: 249–268.

  6. 6

    Mayer P, Hollt V . Allelic and somatic variations in the endogenous opioid system of humans. Pharmacol Ther 2001; 91: 167–177.

  7. 7

    Kreek MJ, Nielsen DA, LaForge KS . Genes associated with addiction: alcoholism, opiate, and cocaine addiction. Neuromolecular Med 2004; 5: 85–108.

  8. 8

    Kreek MJ, Bart G, Lilly C, LaForge KS, Nielsen DA . Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev 2005; 57: 1–26.

  9. 9

    Kreek MJ, Nielsen DA, Butelman ER, LaForge KS . Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction. Nat Neurosci 2005; 8: 1450–1457.

  10. 10

    Bart G, Heilig M, LaForge KS, Pollak L, Leal SM, Ott J et al. Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol Psychiatry 2004; 9: 547–549.

  11. 11

    Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998; 95: 9608–9613.

  12. 12

    Szeto CY, Tang NL, Lee DT, Stadlin A . Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 2001; 12: 1103–1106.

  13. 13

    Yuferov V, Fussell D, LaForge KS, Nielsen DA, Gordon D, Ho A et al. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics 2004; 14: 793–804.

  14. 14

    Li T, Liu X, Zhao J, Hu X, Ball DM, Loh el W et al. Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects. Am J Med Genet 2002; 114: 329–335.

  15. 15

    Lawford BR, Young RM, Noble EP, Sargent J, Rowell J, Shadforth S et al. The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment. Am J Med Genet 2000; 96: 592–598.

  16. 16

    Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y et al. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry 2004; 61: 597–606.

  17. 17

    Kotler M, Cohen H, Segman R, Gritsenko I, Nemanov L, Lerer B et al. Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. Mol Psychiatry 1997; 2: 251–254.

  18. 18

    Li T, Zhu ZH, Liu X, Hu X, Zhao J, Sham PC et al. Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects. Am J Med Genet 2000; 96: 616–621.

  19. 19

    Szilagyi A, Boor K, Szekely A, Gaszner P, Kalasz H, Sasvari-Szekely M et al. Combined effect of promoter polymorphisms in the dopamine D4 receptor and the serotonin transporter genes in heroin dependence. Neuropsychopharmacol Hung 2005; 7: 28–33.

  20. 20

    Li T, Xu K, Deng H, Cai G, Liu J, Liu X et al. Association analysis of the dopamine D4 gene exon III VNTR and heroin abuse in Chinese subjects. Mol Psychiatry 1997; 2: 413–416.

  21. 21

    Gerra G, Garofano L, Santoro G, Bosari S, Pellegrini C, Zaimovic A et al. Association between low-activity serotonin transporter genotype and heroin dependence: behavioral and personality correlates. Am J Med Genet B Neuropsychiatr Genet 2004; 126B: 37–42.

  22. 22

    Tan EC, Yeo BK, Ho BK, Tay AH, Tan CH . Evidence for an association between heroin dependence and a VNTR polymorphism at the serotonin transporter locus. Mol Psychiatry 1999; 4: 215–217.

  23. 23

    Proudnikov D, LaForge KS, Hofflich H, Levenstein M, Gordon D, Barral S et al. Association analysis of polymorphisms in serotonin 1B receptor gene and heroin addiction: a comparison of molecular and statistically estimated haplotypes. Pharmacogenet Genomics 2006; 16: 25–36.

  24. 24

    Cao L, Li T, Xu K, Liu X . Association study of heroin-dependence and −287 A/G polymorphism of catechol-O-methyltransferase gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2002; 19: 499–501.

  25. 25

    Horowitz R, Kotler M, Shufman E, Aharoni S, Kremer I, Cohen H et al. Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family-based haplotype relative risk study. Am J Med Genet 2000; 96: 599–603.

  26. 26

    Long JC, Knowler WC, Hanson RL, Robin RW, Urbanek M, Moore E et al. Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population. Am J Med Genet 1998; 81: 216–221.

  27. 27

    Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, Van Eerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence. Am J Med Genet 1998; 81: 207–215.

  28. 28

    Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B et al. Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 1999; 4: 129–144.

  29. 29

    Foroud T, Edenberg HJ, Goate A, Rice J, Flury L, Koller DL et al. Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping. Alcohol Clin Exp Res 2000; 24: 933–945.

  30. 30

    Stallings MC, Corley RP, Hewitt JK, Krauter KS, Lessem JM, Mikulich SK et al. A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence. Drug Alcohol Depend 2003; 70: 295–307.

  31. 31

    Ehlers CL, Wilhelmsen KC . Genomic scan for alcohol craving in Mission Indians. Psychiatr Genet 2005; 15: 71–75.

  32. 32

    Bierut LJ, Rice JP, Goate A, Hinrichs AL, Saccone NL, Foroud T et al. A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence. Am J Med Genet 2004; 124: 19–27.

  33. 33

    Gelernter J, Panhuysen C, Weiss R, Brady K, Hesselbrock V, Rounsaville B et al. Genomewide linkage scan for cocaine dependence and related traits: significant linkages for a cocaine-related trait and cocaine-induced paranoia. Am J Med Genet B Neuropsychiatr Genet 2005; 136B: 45–52.

  34. 34

    Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, Zhang H . Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking. Am J Med Genet B Neuropsychiatr Genet 2004; 128B: 94–101.

  35. 35

    Gelernter J, Panhuysen C, Wilcox M, Hesselbrock V, Rounsaville B, Poling J et al. Genomewide linkage scan for opioid dependence and related traits. Am J Hum Genet 2006; 78: 759–769.

  36. 36

    Ehlers CL, Wilhelmsen KC . Genomic screen for substance dependence and body mass index in southwest California Indians. Genes Brain Behav 2006; 6: 184–191.

  37. 37

    Ehlers CL, Gilder DA, Wall TL, Phillips E, Feiler H, Wilhelmsen KC . Genomic screen for loci associated with alcohol dependence in Mission Indians. Am J Med Genet B Neuropsychiatr Genet 2004; 129B: 110–115.

  38. 38

    Guerrini I, Cook CC, Kest W, Devitgh A, McQuillin A, Curtis D et al. Genetic linkage analysis supports the presence of two susceptibility loci for alcoholism and heavy drinking on chromosome 1p22.1-11.2 and 1q21.3-24.2. BMC Genet 2005; 6: 11.

  39. 39

    Glatt SJ, Su JA, Zhu SC, Zhang R, Zhang B, Li J et al. Genome-wide linkage analysis of heroin dependence in Han Chinese: results from wave one of a multi-stage study. Am J Med Genet B Neuropsychiatr Genet 2006; 141: 648–652.

  40. 40

    Hu N, Wang C, Hu Y, Yang HH, Giffen C, Tang ZZ et al. Genome-wide association study in esophageal cancer using GeneChip mapping 10K array. Cancer Res 2005; 65: 2542–2546.

  41. 41

    Lachman HM, Fann CS, Bartzis M, Evgrafov OV, Rosenthal RN, Nunes EV et al. Genomewide suggestive linkage of opioid dependence to chromosome 14q. Hum Mol Genet 2007; 16: 1327–1334.

  42. 42

    Uhl GR, Liu QR, Walther D, Hess J, Naiman D . Polysubstance abuse-vulnerability genes: genome scans for association, using 1004 subjects and 1494 single-nucleotide polymorphisms. Am J Hum Genet 2001; 69: 1290–1300.

  43. 43

    Liu QR, Drgon T, Walther D, Johnson C, Poleskaya O, Hess J et al. Pooled association genome scanning: validation and use to identify addiction vulnerability loci in two samples. Proc Natl Acad Sci USA 2005; 102: 11864–11869.

  44. 44

    Johnson C, Drgon T, Liu QR, Walther D, Edenberg H, Rice J et al. Pooled association genome scanning for alcohol dependence using 104,268 SNPs: validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 844–853.

  45. 45

    Liu QR, Drgon T, Johnson C, Walther D, Hess J, Uhl GR . Addiction molecular genetics: 639,401 SNP whole genome association identifies many ‘cell adhesion’ genes. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 918–925.

  46. 46

    McLellan AT, Luborsky L, Woody GE, O'Brien CP . An improved diagnostic evaluation instrument for substance abuse patients. The addiction severity index. J Nerv Ment Dis 1980; 168: 26–33.

  47. 47

    Rettig RA, Yarmolinsky A (eds). Federal Regulation of Methadone Treatment. National Academy Press: Washington, DC, 1995.

  48. 48

    Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

  49. 49

    Lao O, van Duijn K, Kersbergen P, de Knijff P, Kayser M . Proportioning whole-genome single-nucleotide-polymorphism diversity for the identification of geographic population structure and genetic ancestry. Am J Hum Genet 2006; 78: 680–690.

  50. 50

    Storey JD, Tibshirani R . Statistical significance for genome-wide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

  51. 51

    Storey JD, Taylor JE, Siegmund D . Strong control, conservative point estimation, and simultaneous conservative consistency of false discovery rates: A unified approach. J R Statist Soc B 2004; 66: 187–205.

  52. 52

    Collins A, Lonjou C, Morton NE . Genetic epidemiology of single-nucleotide polymorphisms. Proc Natl Acad Sci USA 1999; 96: 15173–15177.

  53. 53

    Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ et al. Linkage disequilibrium in the human genome. Nature 2001; 411: 199–204.

  54. 54

    Schug J, Overton GC . Computational Biology and Informatics Laboratory, School of Medicine, University of Pennsylvania, 1977. Technical Report CBIL-TR-1997-1001-v0.0,

  55. 55

    King DC, Taylor J, Elnitski L, Chiaromonte F, Miller W, Hardison RC . Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences. Genome Res 2005; 15: 1051–1060.

  56. 56

    Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA et al. Genetic structure of human populations. Science 2002; 298: 2381–2385.

  57. 57

    Hattori E, Liu C, Zhu H, Gershon ES . Genetic tests of biologic systems in affective disorders. Mol Psychiatry 2005; 10: 719–740.

  58. 58

    ENCODE Project Consortium. Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447: 799–816.

  59. 59

    Sklan EH, Lowenthal A, Korner M, Ritov Y, Landers DM, Rankinen T et al. Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study. Proc Natl Acad Sci USA 2004; 101: 5512–5517.

  60. 60

    Tosic M, Ott J, Barral S, Bovet P, Deppen P, Gheorghita F et al. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 2006; 79: 586–592.

  61. 61

    Moore JH, Ritchie MD . STUDENTJAMA. The challenges of whole-genome approaches to common diseases. JAMA 2004; 291: 1642–1643.

  62. 62

    Hoh J, Ott J . Mathematical multi-locus approaches to localizing complex human trait genes. Nat Rev Genet 2003; 4: 701–709.

  63. 63

    Pipes GCT, Creemers EE, Olson EN . The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev 2006; 20: 1545–1556.

  64. 64

    Kim B, Koo H, Yang SP, Bang S, Jung Y, Kim YK et al. TC1(C8orf4) correlates with Wnt/{beta}-catenin target genes and aggressive biological behavior in gastric cancer. Clin Cancer Res 2006; 12: 3541–3548.

Download references


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).

Author information

Correspondence to D A Nielsen.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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/

Download citation


  • addiction
  • gene
  • heroin
  • microarray
  • polymorphism

Further reading