Skip to main content

OPRD1 Genetic Variation and Human Disease

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 247)

Abstract

The OPRD1 gene encodes the delta-opioid receptor, which has multiple functions including regulating reward pathways. The gene contains more than 2,000 verified genetic variants but only 2 currently have evidence for specific functions: rs1042114 disrupts maturation of the receptor and rs569356 affects OPRD1 expression. These polymorphisms and others in the gene have been found to be associated with human diseases. The most reproducible data are associations between opioid addiction and three variants in intron 1 (rs2236861, rs2236857, and rs3766951), which have been described in a number of independent populations. Several publications also point toward an association between anorexia and a haplotype block containing rs569356 and rs533123. Unfortunately the mechanisms underlying these two effects are currently unknown. In contrast, rs1042114 has been linked to Alzheimer’s disease through an increasingly well-defined mechanism by which the variant allele reduces production of the beta-amyloid plaques associated with the disease. Additional studies of OPRD1 variants are necessary to replicate current findings and to delineate the functional roles of relevant polymorphisms.

Keywords

  • Addiction
  • Alzheimer’s disease
  • Anorexia
  • Delta opioid receptor
  • OPRD1

This is a preview of subscription content, access via your institution.

Fig. 1

References

  • Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377(9770):1019–1031

    CrossRef  Google Scholar 

  • Beer B, Erb R, Pavlic M, Ulmer H, Giacomuzzi S, Riemer Y et al (2013) Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study. PLoS One 8(9):e75359

    CAS  CrossRef  Google Scholar 

  • Bergen AW, van den Bree MB, Yeager M, Welch R, Ganjei JK, Haque K et al (2003) Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. Mol Psychiatry 8(4):397–406

    CAS  CrossRef  Google Scholar 

  • Boraska V, Davis OS, Cherkas LF, Helder SG, Harris J, Krug I et al (2012) Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits. Am J Med Genet B Neuropsychiatr Genet 159B(7):803–811

    CrossRef  Google Scholar 

  • Boraska V, Franklin CS, Floyd JA, Thornton LM, Huckins LM, Southam L et al (2014) A genome-wide association study of anorexia nervosa. Mol Psychiatry 19(10):1085–1094

    CAS  CrossRef  Google Scholar 

  • Brown KM, Bujac SR, Mann ET, Campbell DA, Stubbins MJ, Blundell JE (2007) Further evidence of association of OPRD1 & HTR1D polymorphisms with susceptibility to anorexia nervosa. Biol Psychiatry 61(3):367–373

    CAS  CrossRef  Google Scholar 

  • Clarke TK, Crist RC, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ et al (2014) Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females. Pharmacogenomics J 14(3):303–308

    CAS  CrossRef  Google Scholar 

  • Crist RC, Ambrose-Lanci LM, Vaswani M, Clarke TK, Zeng A, Yuan C et al (2013a) Case-control association analysis of polymorphisms in the delta-opioid receptor, OPRD1, with cocaine and opioid addicted populations. Drug Alcohol Depend 127(1–3):122–128

    CAS  CrossRef  Google Scholar 

  • Crist RC, Clarke TK, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ et al (2013b) An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology 38(10):2003–2010

    CAS  CrossRef  Google Scholar 

  • Edenberg HJ (2011) Common and rare variants in alcohol dependence. Biol Psychiatry 70(6):498–499

    CrossRef  Google Scholar 

  • Franke P, Nothen MM, Wang T, Neidt H, Knapp M, Lichtermann D et al (1999) Human delta-opioid receptor gene and susceptibility to heroin and alcohol dependence. Am J Med Genet 88(5):462–464

    CAS  CrossRef  Google Scholar 

  • Grice DE, Halmi KA, Fichter MM, Strober M, Woodside DB, Treasure JT et al (2002) Evidence for a susceptibility gene for anorexia nervosa on chromosome 1. Am J Hum Genet 70(3):787–792

    CAS  CrossRef  Google Scholar 

  • Hadjiconstantinou M, Neff NH (2011) Nicotine and endogenous opioids: neurochemical and pharmacological evidence. Neuropharmacology 60(7–8):1209–1220

    CAS  CrossRef  Google Scholar 

  • Herz A (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl) 129(2):99–111

    CAS  CrossRef  Google Scholar 

  • Janecka A, Fichna J, Janecki T (2004) Opioid receptors and their ligands. Curr Top Med Chem 4(1):1–17

    CAS  CrossRef  Google Scholar 

  • Kaye WH, Lilenfeld LR, Berrettini WH, Strober M, Devlin B, Klump KL et al (2000) A search for susceptibility loci for anorexia nervosa: methods and sample description. Biol Psychiatry 47(9):794–803

    CAS  CrossRef  Google Scholar 

  • Kendler KS, Jacobson KC, Prescott CA, Neale MC (2003) 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 160(4):687–695

    CrossRef  Google Scholar 

  • Kvaloy K, Kulle B, Romundstad P, Holmen TL (2013) Sex-specific effects of weight-affecting gene variants in a life course perspective – the HUNT study, Norway. Int J Obes (Lond) 37(9):1221–1229

    CAS  CrossRef  Google Scholar 

  • Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458

    CAS  CrossRef  Google Scholar 

  • Leskela TT, Markkanen PM, Alahuhta IA, Tuusa JT, Petaja-Repo UE (2009) Phe27Cys polymorphism alters the maturation and subcellular localization of the human delta opioid receptor. Traffic 10(1):116–129

    CAS  CrossRef  Google Scholar 

  • Leskela TT, Lackman JJ, Vierimaa MM, Kobayashi H, Bouvier M, Petaja-Repo UE (2012) Cys-27 variant of human delta-opioid receptor modulates maturation and cell surface delivery of Phe-27 variant via heteromerization. J Biol Chem 287(7):5008–5020

    CrossRef  Google Scholar 

  • Levran O, Londono D, O’Hara K, Nielsen DA, Peles E, Rotrosen J et al (2008) Genetic susceptibility to heroin addiction: a candidate gene association study. Genes Brain Behav 7(7):720–729

    CAS  CrossRef  Google Scholar 

  • Li Z, Zhang H (2013) Analyzing interaction of mu-, delta- and kappa-opioid receptor gene variants on alcohol or drug dependence using a pattern discovery-based method. J Addict Res Ther Suppl 7:007

    PubMed  PubMed Central  Google Scholar 

  • Loh el W, Fann CS, Chang YT, Chang CJ, Cheng AT (2004) Endogenous opioid receptor genes and alcohol dependence among Taiwanese Han. Alcohol Clin Exp Res 28(1):15–19

    CrossRef  Google Scholar 

  • Maddalena A, Papassotiropoulos A, Muller-Tillmanns B, Jung HH, Hegi T, Nitsch RM et al (2003) Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol 60(9):1202–1206

    CrossRef  Google Scholar 

  • Maher BS, Vladimirov VI, Latendresse SJ, Thiselton DL, McNamee R, Kang M et al (2011) The AVPR1A gene and substance use disorders: association, replication, and functional evidence. Biol Psychiatry 70(6):519–527

    CAS  CrossRef  Google Scholar 

  • Mathes WF, Brownley KA, Mo X, Bulik CM (2009) The biology of binge eating. Appetite 52(3):545–553

    CAS  CrossRef  Google Scholar 

  • Mathieu-Kia AM, Fan LQ, Kreek MJ, Simon EJ, Hiller JM (2001) Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer’s disease patients. Brain Res 893(1–2):121–134

    CAS  CrossRef  Google Scholar 

  • Mayer P, Rochlitz H, Rauch E, Rommelspacher H, Hasse HE, Schmidt S et al (1997) Association between a delta opioid receptor gene polymorphism and heroin dependence in man. Neuroreport 8(11):2547–2550

    CAS  CrossRef  Google Scholar 

  • Merikangas KR, Stolar M, Stevens DE, Goulet J, Preisig MA, Fenton B et al (1998) Familial transmission of substance use disorders. Arch Gen Psychiatry 55(11):973–979

    CAS  CrossRef  Google Scholar 

  • Nelson EC, Lynskey MT, Heath AC, Wray N, Agrawal A, Shand FL et al (2012) Association of OPRD1 polymorphisms with heroin dependence in a large case-control series. Addict Biol 19:111–121

    CrossRef  Google Scholar 

  • Ripke S (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427

    CAS  CrossRef  Google Scholar 

  • Roussotte FF, Jahanshad N, Hibar DP, Sowell ER, Kohannim O, Barysheva M et al (2014) A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: replication in elderly and young populations. Hum Brain Mapp 35(4):1226–1236

    CrossRef  Google Scholar 

  • Sala L, Mirabel-Sarron C, Pham-Scottez A, Blanchet A, Rouillon F, Gorwood P (2012) Body dissatisfaction is improved but the ideal silhouette is unchanged during weight recovery in anorexia nervosa female inpatients. Eat Weight Disord 17(2):e109–e115

    CAS  CrossRef  Google Scholar 

  • Sarajarvi T, Tuusa JT, Haapasalo A, Lackman JJ, Sormunen R, Helisalmi S et al (2011) Cysteine 27 variant of the delta-opioid receptor affects amyloid precursor protein processing through altered endocytic trafficking. Mol Cell Biol 31(11):2326–2340

    CAS  CrossRef  Google Scholar 

  • Sarajarvi T, Marttinen M, Natunen T, Kauppinen T, Makinen P, Helisalmi S et al (2015) Genetic variation in delta-opioid receptor associates with increased beta- and gamma-secretase activity in the late stages of Alzheimer’s disease. J Alzheimers Dis 48(2):507–516

    CrossRef  Google Scholar 

  • Teng L, Zhao J, Wang F, Ma L, Pei G (2010) A GPCR/secretase complex regulates beta- and gamma-secretase specificity for Abeta production and contributes to AD pathogenesis. Cell Res 20(2):138–153

    CAS  CrossRef  Google Scholar 

  • Wang K, Zhang H, Bloss CS, Duvvuri V, Kaye W, Schork NJ et al (2011) A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa. Mol Psychiatry 16(9):949–959

    CAS  CrossRef  Google Scholar 

  • Xu K, Liu XH, Nagarajan S, Gu XY, Goldman D (2002) Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Am J Med Genet 110(1):45–50

    CrossRef  Google Scholar 

  • Xuei X, Flury-Wetherill L, Bierut L, Dick D, Nurnberger J Jr, Foroud T et al (2007) The opioid system in alcohol and drug dependence: family-based association study. Am J Med Genet B Neuropsychiatr Genet 144B(7):877–884

    CAS  CrossRef  Google Scholar 

  • Yoo JH, Kitchen I, Bailey A (2012) The endogenous opioid system in cocaine addiction: what lessons have opioid peptide and receptor knockout mice taught us? Br J Pharmacol 166(7):1993–2014

    CAS  CrossRef  Google Scholar 

  • Zhang H, Kranzler HR, Yang BZ, Luo X, Gelernter J (2008) The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Mol Psychiatry 13(5):531–543

    CAS  CrossRef  Google Scholar 

  • Zhang H, Gelernter J, Gruen JR, Kranzler HR, Herman AI, Simen AA (2010) Functional impact of a single-nucleotide polymorphism in the OPRD1 promoter region. J Hum Genet 55(5):278–284

    CAS  CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard C. Crist .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Crist, R.C., Clarke, TK. (2016). OPRD1 Genetic Variation and Human Disease. In: Jutkiewicz, E. (eds) Delta Opioid Receptor Pharmacology and Therapeutic Applications. Handbook of Experimental Pharmacology, vol 247. Springer, Cham. https://doi.org/10.1007/164_2016_112

Download citation