Abstract
Opioid addiction is a complicated and highly heritable brain disease. Dysfunction in dopaminergic signaling is involved in the pathogenesis of addictive disorders. Encoding a dopamine synthetase, the tyrosine hydroxylase (TH) gene has long been an interesting candidate in genetic association studies for opioid addiction. However, the mechanisms underlying associations of risk gene variants and opioid addiction remain unknown. In the present study, we first analyzed the association between TH gene variants and susceptibility and traits of heroin addiction in 801 patients with heroin addiction and 930 healthy controls. Methylation levels in the promoter region of the TH gene were detected and compared between the heroin addiction and healthy control groups. To reveal the potential mechanism of the association of TH gene variants and heroin addiction, correlations between the risk TH single nucleotide polymorphism (SNPs) for heroin addiction and the methylation and expression levels of the TH gene were examined. Our results demonstrated that SNP rs6356 was associated with susceptibility to heroin addiction. CpG TH_15 was hypermethylated in the heroin addiction group compared with the healthy control group. Notably, SNP rs6356 was correlated in an allele-specific manner with expression of the TH gene in the hippocampus and nucleus accumbens but not with methylation levels of CpG TH_15. Our findings suggest that the eQTL rs6356 was associated with susceptibility to heroin addiction by potentially affecting the expression of the TH gene in brain regions in the mesocorticolimbic dopamine system, including the hippocampus and nucleus accumbens.
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Availability of Data and Materials
All data and materials will be available upon reasonable request. The sequencing data of the methylation assaying has been deposited into Sequence Read Archive (SRA) under accession number PRJNA752473.
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We thank all the participants for their contributions to the research.
Funding
This work was supported by the Natural Science Foundation of Shaanxi Province (No. 2021JQ-065, 2021JM-028, and 2020JQ-802) and the Young Talent Promotion Program of Shaanxi Science and Technology Association (No. 20200301).
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Jianbo Zhang and Yongsheng Zhu conceptualized this study. Kena Wang and Hongbo Zhang analyzed the data and drafted the manuscript. Jinshan Ji and Rui Zhang contributed to the methodology. Wei Dang and Qiaoli Xie reviewed and edited the manuscript. All the authors reviewed and approved the final version of publication.
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Our study was approved by the Medical Ethics Committees of Xi’an Jiaotong University and the Xi’an Mental Health Center, in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). All study subjects were well informed and provided written informed consent for participating in the study.
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Wang, K., Zhang, H., Ji, J. et al. Expression Quantitative Trait Locus rs6356 Is Associated with Susceptibility to Heroin Addiction by Potentially Influencing TH Gene Expression in the Hippocampus and Nucleus Accumbens. J Mol Neurosci 72, 1108–1115 (2022). https://doi.org/10.1007/s12031-022-01992-1
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DOI: https://doi.org/10.1007/s12031-022-01992-1