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Population-specific genetic background for the OPRM1 variant rs1799971 (118A>G): implications for genomic medicine and functional analysis

Molecular Psychiatry volume 26, pages 3169–3177 (2021)Cite this article

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Abstract

The mu-opioid receptor (MOR, OPRM1) has important roles in diverse functions including reward, addiction, and response to pain treatment. SNP rs1799971 (118A > G, N40D) which occur at a high frequency (40–60%) in Asia and moderate frequency (15%) in samples of European ancestry, is the only common coding variant in the canonical transcript, in non-African populations. Despite extensive studies, the molecular consequences of this variation remained unresolved. The aim of this study was to determine the genetic background of the OPRM1 region of 118G in four representative populations and to assess its potential modulatory effect. Seven common haplotypes with distinct population distribution were identified based on seven SNPs. Three haplotypes carry the 118G and additional highly linked regulatory SNPs (e.g., rs9383689) that could modulate the effect of 118G. Extended analysis in the 1000 Genomes database (n = 2504) revealed a common East Asian-specific haplotype with a different genetic background in which there are no variant alleles for an upstream LD block tagged by the eQTL rs9397171. The major European haplotype specifically includes the eQTL intronic SNP rs62436463 that must have arisen after the split between European and Asian populations. Differentiating between the effect of 118G and these SNPs requires specific experimental approaches. The analysis also revealed a significant increase in two 118A haplotypes with eQTL SNPs associated with drug addiction (rs510769) and obesity (rs9478496) in populations with native Mexican ancestry. Future studies are required to assess the clinical implication of these findings.

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Fig. 1: Schematic of the OPRM1 gene structure, SNPs locations, LD blocks, and selected alternative splice variants.
Fig. 2: The relative distribution of the seven major haplotypes in the four selected samples.
Fig. 3: SNP rs1799971 (118G) haplotypes (#5-7).

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References

  1. Prohaska A, Racimo F, Schork AJ, Sikora M, Stern AJ, Ilardo M, et al. Human disease variation in the light of population genomics. Cell. 2019;177:115–31.

    Article  CAS  PubMed  Google Scholar 

  2. Crist RC, Reiner BC, Berrettini WH. A review of opioid addiction genetics. Curr Opin Psychol. 2019;27:31–5.

    Article  PubMed  Google Scholar 

  3. Kreek MJ, Levran O, Reed B, Schlussman SD, Zhou Y, Butelman ER. Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics. J Clin Invest. 2012;122:3387–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pasternak GW, Pan YX. Mu opioids and their receptors: evolution of a concept. Pharm Rev. 2013;65:1257–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lopez Soto EJ, Catanesi CI. Human population genetic structure detected by pain-related mu opioid receptor gene polymorphisms. Genet Mol Biol. 2015;38:152–5.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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;95:9608–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Burns JA, Kroll DS, Feldman DE, Kure Liu C, Manza P, Wiers CE, et al. Molecular imaging of opioid and dopamine systems: insights into the pharmacogenetics of opioid use disorders. Front Psychiatry. 2019;10:626.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Levran O, Yuferov V, Kreek MJ. The genetics of the opioid system and specific drug addictions. Hum Genet. 2012;131:823–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mague SD, Blendy JA. OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug Alcohol Depend. 2010;108:172–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang X, Liang Y, Zhang N, Yan Y, Liu S, Fengxi H, et al. The relevance of the OPRM1 118A>G genetic variant for opioid requirement in pain treatment: a meta-analysis. Pain Physician. 2019;22:331–40.

    PubMed  Google Scholar 

  11. Ray LA, Barr CS, Blendy JA, Oslin D, Goldman D, Anton RF. The role of the Asn40Asp polymorphism of the mu opioid receptor gene (OPRM1) on alcoholism etiology and treatment: a critical review. Alcohol Clin Exp Res. 2012;36:385–94.

    Article  CAS  PubMed  Google Scholar 

  12. Haerian BS, Haerian MS. OPRM1 rs1799971 polymorphism and opioid dependence: evidence from a meta-analysis. Pharmacogenomics. 2013;14:813–24.

    Article  CAS  PubMed  Google Scholar 

  13. Chen D, Liu L, Xiao Y, Peng Y, Yang C, Wang Z. Ethnic-specific meta-analyses of association between the OPRM1 A118G polymorphism and alcohol dependence among Asians and Caucasians. Drug Alcohol Depend. 2012;123:1–6.

    Article  CAS  PubMed  Google Scholar 

  14. Mura E, Govoni S, Racchi M, Carossa V, Ranzani GN, Allegri M, et al. Consequences of the 118A>G polymorphism in the OPRM1 gene: translation from bench to bedside? J Pain Res. 2013;6:331–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pecina M, Zubieta JK. Expectancy modulation of opioid neurotransmission. Int Rev Neurobiol. 2018;138:17–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fournier T, Schacherer J. Genetic backgrounds and hidden trait complexity in natural populations. Curr Opin Genet Dev. 2017;47:48–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hwang IC, Park JY, Myung SK, Ahn HY, Fukuda K, Liao Q. OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis. Anesthesiology. 2014;121:825–34.

    Article  PubMed  Google Scholar 

  18. Hernandez-Avila CA, Covault J, Wand G, Zhang H, Gelernter J, Kranzler HR. Population-specific effects of the Asn40Asp polymorphism at the mu-opioid receptor gene (OPRM1) on HPA-axis activation. Pharmacogenet Genomics. 2007;17:1031–8.

    Article  CAS  PubMed  Google Scholar 

  19. Genomes Project Consortium, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Article  CAS  Google Scholar 

  20. Levran O, Awolesi O, Linzy S, Adelson M, Kreek MJ. Haplotype block structure of the genomic region of the mu opioid receptor gene. J Hum Genet. 2011;56:147–55.

    Article  CAS  PubMed  Google Scholar 

  21. Levran O, Even-Tov E, Zhao L. A hominid-specific shift in cerebellar expression, upstream retrotransposons, and a potential cis-regulatory mechanism: bioinformatics analyses of the mu-opioid receptor gene. Heredity. 2020;124:325–35.

    Article  CAS  PubMed  Google Scholar 

  22. Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45:580.

    Article  CAS  Google Scholar 

  23. Norris ET, Wang L, Conley AB, Rishishwar L, Marino-Ramirez L, Valderrama-Aguirre A, et al. Genetic ancestry, admixture and health determinants in Latin America. BMC Genomics. 2018;19:861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Levran O, Londono D, O’Hara K, Nielsen DA, Peles E, Rotrosen J, et al. Genetic susceptibility to heroin addiction: a candidate gene association study. Genes Brain Behav. 2008;7:720–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hancock DB, Levy JL, Gaddis NC, Glasheen C, Saccone NL, Page GP, et al. Cis-expression quantitative trait loci mapping reveals replicable associations with heroin addiction in OPRM1. Biol Psychiatry. 2015;78:474–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tolami HF, Sharafshah A, Tolami LF, Keshavarz P. Haplotype-based association and in silico studies of OPRM1 gene variants with susceptibility to opioid dependence among addicted iranians undergoing methadone treatment. J Mol Neurosci. 2020;70:504–13.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang H, Luo X, Kranzler HR, Lappalainen J, Yang BZ, Krupitsky E, et al. Association between two mu-opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet. 2006;15:807–19.

    Article  CAS  PubMed  Google Scholar 

  28. Lappalainen T, Montgomery SB, Nica AC, Dermitzakis ET. Epistatic selection between coding and regulatory variation in human evolution and disease. Am J Hum Genet. 2011;89:459–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hartwell EE, Feinn R, Morris PE, Gelernter J, Krystal J, Arias AJ et al. Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder. Addiction 2020.

  30. Xu J, Xu M, Hurd YL, Pasternak GW, Pan YX. Isolation and characterization of new exon 11-associated N-terminal splice variants of the human mu opioid receptor gene. J Neurochem. 2009;108:962–72.

    Article  CAS  PubMed  Google Scholar 

  31. Tishkoff SA, Reed FA, Friedlaender FR, Ehret C, Ranciaro A, Froment A, et al. The genetic structure and history of Africans and African Americans. Science. 2009;324:1035–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Avila-Arcos MC, McManus KF, Sandoval K, Rodriguez-Rodriguez JE, Villa-Islas V, Martin AR, et al. Population History and Gene Divergence in Native Mexicans Inferred from 76 Human Exomes. Mol Biol Evol. 2020;37:994–1006.

    Article  CAS  PubMed  Google Scholar 

  33. Ducat E, Ray B, Bart G, Umemura Y, Varon J, Ho A, et al. Mu-opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone. Addict Biol. 2013;18:325–31.

    Article  CAS  PubMed  Google Scholar 

  34. Chong RY, Oswald L, Yang X, Uhart M, Lin PI, Wand GS. The mu-opioid receptor polymorphism A118G predicts cortisol responses to naloxone and stress. Neuropsychopharmacology. 2006;31:204–11.

    Article  CAS  PubMed  Google Scholar 

  35. Wand GS, McCaul M, Yang X, Reynolds J, Gotjen D, Lee S, et al. The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade. Neuropsychopharmacology. 2002;26:106–14.

    Article  CAS  PubMed  Google Scholar 

  36. Halikere A, Popova D, Scarnati MS, Hamod A, Swerdel MR, Moore JC, et al. Addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons. Mol Psychiatry. 2020;25:1406–19.

    Article  CAS  PubMed  Google Scholar 

  37. Gallagher MD, Chen-Plotkin AS. The Post-GWAS Era: from association to function. Am J Hum Genet. 2018;102:717–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kichaev G, Bhatia G, Loh PR, Gazal S, Burch K, Freund MK, et al. Leveraging polygenic functional enrichment to improve GWAS power. Am J Hum Genet. 2019;104:65–75.

    Article  CAS  PubMed  Google Scholar 

  39. Tian C, Gregersen PK, Seldin MF. Accounting for ancestry: population substructure and genome-wide association studies. Hum Mol Genet. 2008;17:R143–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bodnar RJ. Endogenous opioid modulation of food intake and body weight: Implications for opioid influences upon motivation and addiction. Peptides. 2019;116:42–62.

    Article  CAS  PubMed  Google Scholar 

  41. Sweeney CG, Rando JM, Panas HN, Miller GM, Platt DM, Vallender EJ. Convergent balancing selection on the mu-opioid receptor in primates. Mol Biol Evol. 2017;34:1629–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Crystal HA, Hamon S, Randesi M, Cook J, Anastos K, Lazar J, et al. A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women. Addict Biol. 2012;17:181–91.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

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  1. Laboratory on the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA

    Orna Levran & Mary Jeanne Kreek

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Correspondence to Orna Levran.

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Levran, O., Kreek, M.J. Population-specific genetic background for the OPRM1 variant rs1799971 (118A>G): implications for genomic medicine and functional analysis. Mol Psychiatry 26, 3169–3177 (2021). https://doi.org/10.1038/s41380-020-00902-4

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