Jianbo Zhang1,2, Yajuan Fan3, Jinting Zhou1,2, Tengfei Ma4, Keqiang Gao4, Min Xu4, Yifan Xiao1,2, Yongsheng Zhu5,6. 1. Key Laboratory of National Health Commission for Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. 2. Bio-evidence Sciences Academy, Xi'an Jiaotong University, Xi'an, 712000, Shaanxi, China. 3. The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. 4. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. 5. Key Laboratory of National Health Commission for Forensic Science, College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. zys3000@xjtu.edu.cn. 6. Bio-evidence Sciences Academy, Xi'an Jiaotong University, Xi'an, 712000, Shaanxi, China. zys3000@xjtu.edu.cn.
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.
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.
Authors: Catherine Do; Charles F Lang; John Lin; Huferesh Darbary; Izabela Krupska; Aulona Gaba; Lynn Petukhova; Jean-Paul Vonsattel; Mary P Gallagher; Robin S Goland; Raphael A Clynes; Andrew Dwork; John G Kral; Catherine Monk; Angela M Christiano; Benjamin Tycko Journal: Am J Hum Genet Date: 2016-05-05 Impact factor: 11.025
Authors: Kaili Anier; Mari Urb; Karin Kipper; Koit Herodes; Tõnis Timmusk; Alexander Zharkovsky; Anti Kalda Journal: Neuropharmacology Date: 2018-06-28 Impact factor: 5.250
Authors: E R Gamazon; J A Badner; L Cheng; C Zhang; D Zhang; N J Cox; E S Gershon; J R Kelsoe; T A Greenwood; C M Nievergelt; C Chen; R McKinney; P D Shilling; N J Schork; E N Smith; C S Bloss; J I Nurnberger; H J Edenberg; T Foroud; D L Koller; W A Scheftner; W Coryell; J Rice; W B Lawson; E A Nwulia; M Hipolito; W Byerley; F J McMahon; T G Schulze; W H Berrettini; J B Potash; P P Zandi; P B Mahon; M G McInnis; S Zöllner; P Zhang; D W Craig; S Szelinger; T B Barrett; C Liu Journal: Mol Psychiatry Date: 2012-01-03 Impact factor: 15.992