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Methylation quantitative trait locus rs5326 is associated with susceptibility and effective dosage of methadone maintenance treatment for heroin use disorder

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Abstract

Rationale

Opioid use disorder is a complicated brain disease with high heritability. The underlying mechanisms of the genetic underpinnings in the susceptibility and treatment response of opioid use disorder remain elusive.

Objectives

To reveal the potential associations of genotypes and gene methylations of dopaminergic system genes, as well as roles of them in opioid use disorder. In the present study, we detected the DNA methylation in the promoter regions of five representative dopaminergic system genes (DRD1, DRD2, SLC6A3, TH, and COMT) between 120 patients with heroin use disorder in methadone maintenance treatment (MMT) program and 111 healthy controls. The associations of 25 SNPs in the above genes and methylation of 237 CpG sites, known as methylation quantitative trait loci (mQTLs), were determined. Then, the correlations of the above mQTLs and traits of heroin use disorder were analyzed in a sample set of 801 patients with heroin use disorder and 930 healthy controls.

Results

Our results demonstrated that several mQTLs in the DRD1 and DRD2 genes were identified both in the heroin use disorder and healthy control groups. Interestingly, rs4867798-CpG_174872884 and rs5326-CpG_174872884 in the DRD1 gene were the unique SNP-CpG pairs in the patients with heroin use disorder. Furthermore, mQTL rs5326 was associated with the susceptibility and effective dosage of MMT for heroin use disorder, and demonstrated allele-specific correlation with the expression of the DRD1 gene in the human caudate.

Conclusions

Our findings suggest that some mQTLs may be associated with traits of opioid use disorder by implicating the DNA methylation and gene expression.

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Data availability

The sequencing data of the methylation assaying in our study has been deposited into Sequence Read Archive (SRA) under accession number PRJNA752473. All data and code will be available upon request.

References

  • Anier K, Urb M, Kipper K, Herodes K, Timmusk T, Zharkovsky A, Kalda A (2018) Cocaine-induced epigenetic DNA modification in mouse addiction-specific and non-specific tissues. Neuropharmacology 139:13–25

    Article  CAS  PubMed  Google Scholar 

  • Browne CJ, Godino A, Salery M, Nestler EJ (2020) Epigenetic mechanisms of opioid addiction. Biol Psychiatry 87:22–33

    Article  CAS  PubMed  Google Scholar 

  • Chang CC, Tsai SJ, Chen NC, Huang CW, Hsu SW, Chang YT, Liu ME, Chang WN, Tsai WC, Lee CC (2018) Catechol-O-methyltransferase Val158Met polymorphism on striatum structural covariance networks in alzheimer's disease. Mol Neurobiol 55:4637–4649

    Article  CAS  PubMed  Google Scholar 

  • Comb M, Goodman HM (1990) CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucleic Acids Res 18:3975–3982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daubner SC, Le T, Wang S (2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 508:1–12

    Article  CAS  PubMed  Google Scholar 

  • De Pirro S, Galati G, Pizzamiglio L, Badiani A (2018) The affective and neural correlates of heroin versus cocaine use in addiction are influenced by environmental setting but in opposite directions. J Neurosci 38:5182–5195

    Article  PubMed  PubMed Central  Google Scholar 

  • Do C, Lang CF, Lin J, Darbary H, Krupska I, Gaba A, Petukhova L, Vonsattel JP, Gallagher MP, Goland RS, Clynes RA, Dwork A, Kral JG, Monk C, Christiano AM, Tycko B (2016) Mechanisms and disease associations of haplotype-dependent allele-specific DNA methylation. Am J Hum Genet 98:934–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doehring A, Oertel BG, Sittl R, Lötsch J (2013) Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain. Pain 154:15–23

    Article  CAS  PubMed  Google Scholar 

  • Fries GR, Li Q, McAlpin B, Rein T, Walss-Bass C, Soares JC, Quevedo J (2016) The role of DNA methylation in the pathophysiology and treatment of bipolar disorder. Neurosci Biobehav Rev 68:474–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gamazon ER, Badner JA, Cheng L, Zhang C, Zhang D, Cox NJ, Gershon ES, Kelsoe JR, Greenwood TA, Nievergelt CM, Chen C, McKinney R, Shilling PD, Schork NJ, Smith EN, Bloss CS, Nurnberger JI, Edenberg HJ, Foroud T et al (2013) Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry 18:340–346

    Article  CAS  PubMed  Google Scholar 

  • Gaunt TR, Shihab HA, Hemani G, Min JL, Woodward G, Lyttleton O, Zheng J, Duggirala A, McArdle WL, Ho K, Ring SM, Evans DM, Davey Smith G, Relton CL (2016) Systematic identification of genetic influences on methylation across the human life course. Genome Biol 17:61

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532

    Article  CAS  PubMed  Google Scholar 

  • Grimm SA, Shimbo T, Takaku M, Thomas JW, Auerbach S, Bennett BD, Bucher JR, Burkholder AB, Day F, Du Y, Duncan CG, French JE, Foley JF, Li J, Merrick BA, Tice RR, Wang T, Xu X, Bushel PR et al (2019) DNA methylation in mice is influenced by genetics as well as sex and life experience. Nature communications 10:305

    Article  PubMed  PubMed Central  Google Scholar 

  • Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Garcia Vizcaino JC, Schuetz AL, Burkhardt S, Benito E, Navarro Sala M, Javan SB, Haass C, Schmid B, Fischer A, Bonn S (2016) DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci 19:102–110

    Article  CAS  PubMed  Google Scholar 

  • Han H, Liu Q, Yang Z, Wang M, Ma Y, Cao L, Cui W, Yuan W, Payne TJ, Li L, Li MD (2018) Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers. Transl Psychiatry 8:243

    Article  PubMed  PubMed Central  Google Scholar 

  • Hannon E, Dempster E, Viana J, Burrage J, Smith AR, Macdonald R, St Clair D, Mustard C, Breen G, Therman S, Kaprio J, Toulopoulou T, Hulshoff Pol HE, Bohlken MM, Kahn RS, Nenadic I, Hultman CM, Murray RM, Collier DA et al (2016) An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation. Genome Biol 17:176

    Article  PubMed  PubMed Central  Google Scholar 

  • Kozlenkov A, Jaffe AE, Timashpolsky A, Apontes P, Rudchenko S, Barbu M, Byne W, Hurd YL, Horvath S, Dracheva S (2017) DNA methylation profiling of human prefrontal cortex neurons in heroin users shows significant difference between genomic contexts of hyper- and hypomethylation and a younger epigenetic age. Genes (Basel) 8

  • Li M, D'Arcy C, Li X, Zhang T, Joober R, Meng X (2019) What do DNA methylation studies tell us about depression? A systematic review. Transl Psychiatry 9:68

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Han H, Wang M, Yao Y, Wen L, Jiang K, Ma Y, Fan R, Chen J, Su K, Yang Z, Cui W, Yuan W, Jiang X, Li J, Payne TJ, Wang J, Li MD (2018) Association and cis-mQTL analysis of variants in CHRNA3-A5, CHRNA7, CHRNB2, and CHRNB4 in relation to nicotine dependence in a Chinese Han population. Transl Psychiatry 8:83

    Article  PubMed  PubMed Central  Google Scholar 

  • Luo R, Li X, Qin S, Luo Z, Luo X, Hu P, Liu Z, Feng X, Li X (2017) Impact of SNP-SNP interaction among ABCB1, ARRB2, DRD1 and OPRD1 on methadone dosage requirement in Han Chinese patients. Pharmacogenomics 18:1659–1670

    Article  CAS  PubMed  Google Scholar 

  • Lüscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69:650–663

    Article  PubMed  PubMed Central  Google Scholar 

  • Macare C, Ducci F, Zhang Y, Ruggeri B, Jia T, Kaakinen M, Kalsi G, Charoen P, Casoni F, Peters J, Bromberg U, Hill M, Buxton J, Blakemore A, Veijola J, Büchel C, Banaschewski T, Bokde ALW, Conrod P et al (2018) A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response. Eur Neuropsychopharmacol 28:1103–1114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madras BK, Miller GM, Fischman AJ (2005) The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1397–1409

    Article  CAS  PubMed  Google Scholar 

  • Mouly S, Bloch V, Peoc'h K, Houze P, Labat L, Ksouda K, Simoneau G, Declèves X, Bergmann JF, Scherrmann JM, Laplanche JL, Lepine JP, Vorspan F (2015) Methadone dose in heroin-dependent patients: role of clinical factors, comedications, genetic polymorphisms and enzyme activity. Br J Clin Pharmacol 79:967–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449

    Article  CAS  PubMed  Google Scholar 

  • Park K, Otte A (2019) Prevention of opioid abuse and treatment of opioid addiction: current status and future possibilities. Annu Rev Biomed Eng 21:61–84

    Article  CAS  PubMed  Google Scholar 

  • Pathak S, Miller J, Morris EC, Stewart WCL, Greenberg DA (2018) DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians. Epilepsia 59:1011–1019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pich EM, Pagliusi SR, Tessari M, Talabot-Ayer D, Hooft van Huijsduijnen R, Chiamulera C (1997) Common neural substrates for the addictive properties of nicotine and cocaine. Science 275:83–86

    Article  CAS  PubMed  Google Scholar 

  • Qian DC, Molfese DL, Jin JL, Titus AJ, He Y, Li Y, Vaissié M, Viswanath H, Baldwin PR, Krahe R, Salas R, Amos CI (2017) Genome-wide imaging association study implicates functional activity and glial homeostasis of the caudate in smoking addiction. BMC Genomics 18:740

    Article  PubMed  PubMed Central  Google Scholar 

  • Randesi M, van den Brink W, Levran O, Yuferov V, Blanken P, van Ree JM, Ott J, Kreek MJ (2018) Dopamine gene variants in opioid addiction: comparison of dependent patients, nondependent users and healthy controls. Pharmacogenomics 19:95–104

    Article  CAS  PubMed  Google Scholar 

  • Schacht JP, Voronin KE, Randall PK, Anton RF (2018) Dopaminergic genetic variation influences aripiprazole effects on alcohol self-administration and the neural response to alcohol cues in a randomized trial. Neuropsychopharmacology 43:1247–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultz W (2016) Reward functions of the basal ganglia. J Neural Transm (Vienna) 123:679–693

    Article  Google Scholar 

  • Self DW, Barnhart WJ, Lehman DA, Nestler EJ (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science 271:1586–1589

    Article  CAS  PubMed  Google Scholar 

  • Shabalin AA (2012) Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics 28:1353–1358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sibley DR, Monsma FJ Jr (1992) Molecular biology of dopamine receptors. Trends Pharmacol Sci 13:61–69

    Article  CAS  PubMed  Google Scholar 

  • Soubry A, Schildkraut JM, Murtha A, Wang F, Huang Z, Bernal A, Kurtzberg J, Jirtle RL, Murphy SK, Hoyo C (2013) Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med 11:29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Svyryd Y, Ramírez-Venegas A, Sánchez-Hernández B, Aguayo-Gómez A, Luna-Muñoz L, Arteaga-Vázquez J, Regalado-Pineda J, Mutchinick OM (2016) Genetic risk determinants for cigarette smoking dependence in Mexican Mestizo families. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 18:620–625

    Article  CAS  Google Scholar 

  • Unnikrishnan A, Freeman WM, Jackson J, Wren JD, Porter H, Richardson A (2019) The role of DNA methylation in epigenetics of aging. Pharmacol Ther 195:172–185

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Leung FC (2004) An evaluation of new criteria for CpG islands in the human genome as gene markers. Bioinformatics 20:1170–1177

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Xing Q, Song B, Li G, Xu Z, Wang T, Chen Y, Xu Y, Cao Y (2020) Aberrant DNA methylation in the PAX2 promoter is associated with Müllerian duct anomalies. Arch Gynecol Obstet 301:1455–1461

    Article  CAS  PubMed  Google Scholar 

  • Yang BZ, Zhang H, Ge W, Weder N, Douglas-Palumberi H, Perepletchikova F, Gelernter J, Kaufman J (2013) Child abuse and epigenetic mechanisms of disease risk. Am J Prev Med 44:101–107

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuan V, Price EM, Del Gobbo G, Mostafavi S, Cox B, Binder AM, Michels KB, Marsit C, Robinson WP (2019) Accurate ethnicity prediction from placental DNA methylation data. Epigenetics Chromatin 12:51

    Article  PubMed  PubMed Central  Google Scholar 

  • Zeng H, Gifford DK (2017) Predicting the impact of non-coding variants on DNA methylation. Nucleic Acids Res 45:e99

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Wang F, Kranzler HR, Yang C, Xu H, Wang Z, Zhao H, Gelernter J (2014) Identification of methylation quantitative trait loci (mQTLs) influencing promoter DNA methylation of alcohol dependence risk genes. Hum Genet 133:1093–1104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Yan P, Li Y, Cai X, Yang Z, Miao X, Chen B, Li S, Dang W, Jia W, Zhu Y (2018) A 35.8 kilobases haplotype spanning ANKK1 and DRD2 is associated with heroin dependence in Han Chinese males. Brain Res 1688:54–64

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Liang X, Zhu F, Wen Y, Xu J, Yang J, Ding M, Cheng B, Ma M, Zhang L, Cheng S, Wu C, Wang S, Wang X, Ning Y, Guo X, Zhang F (2018) A large-scale integrative analysis of GWAS and common meQTLs across whole life course identifies genes, pathways and tissue/cell types for three major psychiatric disorders. Neurosci Biobehav Rev 95:347–352

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Prof. Feng Zhu for his kindly help in sample collection and data analysis.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81571858) and the Open Project Fund of Key Laboratory of the National Health Commission for Forensic Science (No. 2019FYXH002).

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Authors and Affiliations

  1. Key Laboratory of National Health Commission for Forensic Science, College of Forensic Medicine, Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Jianbo Zhang, Jinting Zhou, Yifan Xiao &  Yongsheng Zhu

  2. Bio-evidence Sciences Academy, Xi’an Jiaotong University, Xi’an, 712000, Shaanxi, China

    Jianbo Zhang, Jinting Zhou, Yifan Xiao &  Yongsheng Zhu

  3. The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Yajuan Fan

  4. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Tengfei Ma, Keqiang Gao & Min Xu

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  1. Jianbo Zhang
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  2. Yajuan Fan
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  3. Jinting Zhou
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  4. Tengfei Ma
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  6. Min Xu
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  8. Yongsheng Zhu
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Contributions

Yongsheng Zhu and Jianbo Zhang conceptualized this study. Jianbo Zhang and Yajuan Fan analyzed the data and drafted the original manuscript. Tengfei Ma, Keqiang Gao, and Min Xu reviewed and edited the manuscript. Jinting Zhou and Yifan Xiao contributed to the methodology. All the authors reviewed and approved the final version of the publication.

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Correspondence to Yongsheng Zhu.

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Fig. S1

Schematic diagram of the detected CpG sites and SNPs in the dopaminergic system genes. (PNG 40 kb)

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Zhang, J., Fan, Y., Zhou, J. et al. Methylation quantitative trait locus rs5326 is associated with susceptibility and effective dosage of methadone maintenance treatment for heroin use disorder. Psychopharmacology 238, 3511–3518 (2021). https://doi.org/10.1007/s00213-021-05968-8

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