Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

doi:10.21203/rs.3.rs-1357343/v1

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Research Article

Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

https://doi.org/10.21203/rs.3.rs-1357343/v1

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published 08 Mar, 2022

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Opioid addiction is a complicated and highly heritable brain disease. Dysfunction of dopaminergic signaling is involved in the pathogenesis of addictive disorders. Encoding the synthetase of dopamine, tyrosine hydroxylase (TH) gene has long been an interesting candidate in the genetic association studies for opioid addiction. However, the underlying mechanism of the association of risk gene variants and opioid addiction remains 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. The methylation level in the promoter region of the TH gene was 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, correlation between the risk TH SNPs for heroin addiction and the methylation as well expression level of TH gene were examined. Our results demonstrated that SNP rs6356 was associated with the susceptibility of heroin addiction. CpG TH_15 was hypermethylated in the heroin addiction group compared with the healthy control group. Notably, SNP rs6356 was allele-specific correlated with the expression of TH gene in the hippocampus and nucleus accumbens, but not the methylation level of CpG TH_15. Our findings suggest that the eQTL rs6356 was associated with the risk of heroin addiction by potentially affecting the expression of TH gene in the mesocorticolimbic dopamine system brain regions including hippocampus and nucleus accumbens.

heroin addiction

tyrosine hydroxylase

DNA methylation

methylation quantitative trait locus

expression quantitative trait locus

Substance addiction is a complex brain disease, characterized as compulsive substance seeking, abstinence, and repeated relapse for substance use (Chisholm et al., 2021; Huang, Chen, Lane, Ho, & Chung, 2021). Opioid, one of the most abused prescription medicines for pain management and illicit drugs of addiction, causes the most harm in substance misuse-related deaths, killing tens of thousands people per year alone in America (Browne, Godino, Salery, & Nestler, 2020). In China, more than 730 thousand people have exposed to illicit opioid, mainly heroin in 2020. Mounting evidence has suggested that genetic underpinnings and environmental factors contribute to the development of substance addiction (Gerra et al., 2021). Twin studies reveal that the heritability of opioid addiction is about 70% (Goldman, Oroszi, & Ducci, 2005). Genome-wide association studies have proposed a large amount of risk gene variants for opioid addiction (Song et al., 2020; Zhou et al., 2020). However, the underlying mechanism of the association of risk gene variants and opioid addiction remains unknown.

Prolonged use of addictive substances could lead to adaptive alterations in neural plasticity in discrete brain regions including the mesocorticolimbic dopamine system which processes the reward and motivation effects (Hyman, Malenka, & Nestler, 2006), resulting in the transition to addicted states (Stewart, Fulton, & Maze, 2021). DNA methylation, one of the epigenetic components, represents a mechanism that affects the plasticity process and then the development of substance addiction by involving environmental stimuli and regulating gene expression patterns (Stewart et al., 2021). DNA methylation, especially in the promoter region of the gene where is rich with CpG sites and transcriptional factors binding sites, is an important mechanism that regulates gene expression (Pathak, Miller, Morris, Stewart, & Greenberg, 2018). Genetic variants can be associated with the methylation and expression level of the gene. These variants are known as the methylation quantitative trait locus (mQTL) (Villicaña & Bell, 2021) or expression quantitative trait locus (eQTL) (Degtyareva, Antontseva, & Merkulova, 2021). Previous studies have revealed that the mQTLs and eQTLs are enriched in risk genetic variants in many neuropsychiatric diseases such as schizophrenia (Perzel Mandell et al., 2021; Zhao et al., 2018), depression (Ciuculete et al., 2020; X. Wang et al., 2020), and substance addiction (Lin et al., 2020; H. Zhang et al., 2014). Thus, risk genetic variants that correlated with the methylation or expression of the gene may be important mechanism underlying the association with susceptibility and traits of substance addiction.

Tyrosine hydroxylase (TH) is a key rate-limiting enzyme in dopamine and norepinephrine biosynthesis (Boundy et al., 1998; Walters, Kuo, & Blendy, 2003). By regulating the level of the above neurotransmitters with essential roles in neuronal activity, TH has been shown involved in many neuropsychiatric disorders including opioid addiction (Jalali Mashayekhi, Rasti, Khoshdel, & Owji, 2018; Vaillancourt et al., 2021). Repeated morphine administration increased the TH expression in hippocampus (Fang et al., 2017) and locus coeruleus (Jalali Mashayekhi et al., 2018), which are important brain regions in mesocorticolimbic dopamine system. Aldehyde dehydrogenase 2 (ALDH2) inhibitor could prevent the reinstatement of cocaine and alcohol intake by suppressing the activated (phosphorylated) tyrosine hydroxylase signaling (Diamond & Yao, 2015). Hence, TH gene has long been an interesting candidate for the genetic association studies for opioid addiction. However, few studies have elucidated the underlying mechanism in it.

In the present study, we first determined the association between TH gene variants and susceptibility of heroin addiction. Then, the association of TH gene variants and traits of heroin addiction were analyzed. To reveal the potential mechanism of the association between risk SNPs in the TH gene and heroin addiction, we detected and compared the methylation level in the promoter region of the TH gene. Association analysis between the risk SNPs and the methylation level of CpG sites with differential methylation between patients with heroin addiction and healthy controls were performed. Finally, the risk SNPs were screened in the genotype-tissue expression (GTEx) database to demonstrate whether they were eQTLs in human brain regions.

2.1 Study subjects

A total of 1731 unrelated Northwestern Han Chinese participated in the present study. In the heroin addiction group, 801 patients in the methadone maintenance treatment (MMT) Program were recruited from Xi’an Mental Health Center. All patients were diagnosed by senior psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, Five Revision (DSM-VR). Patients with other substances addiction including tobacco and alcohol, or subjected to other psychiatric disorders were excluded. Demographic information including age, gender, marital status, education, occupation, income and family relation (Table S1 and S2), as well as traits of heroin addiction including the age of onset for heroin use, heroin dose per time, heroin intake times per day, duration from first heroin exposure to addiction and effective methadone dose (Table S3) were collected by questionnaire survey to the patients. Regarding the healthy control group, 930 healthy subjects were enrolled from the Health Examination Centers of the First Affiliated Hospital of Xi’an Jiaotong University and Tangdu Hospital. They had no substances (including tobacco and alcohol) addiction, no personal or family history of psychiatric disorders, or severe organic diseases. There were no age and gender distribution differences between groups (Table S1).

All study subjects were well informed and provided written informed consent for participating in the study. The protocol of 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).

2.2 SNP selection and DNA extraction

For the analysis of association between TH gene variants and risk of heroin addiction, tag SNPs in the functional region (promoter region, untranslated regions, exons, and intron-exon boundaries) of the TH gene that with minor allele frequency (MAF) > 0.05 and minor genotype frequency > 0.01 in the Han Chinese population of the 1000 Genomes database were selected. For the association analysis of TH gene variants and traits of heroin addiction, all functional SNPs with frequencies meeting the above criteria were genotyped in the heroin addiction group. In addition, all SNPs should meet Hardy-Weinberg equilibrium (HWE) in the healthy control group.

Genome DNA was extracted from the peripheral blood with the EZNA™ Blood DNA Midi Kit (Omega Bio-TeK, Norcross, GA, USA) according to the manufacturer’s instructions. Following quality control, the DNA was subjected to SNP genotyping and detection of DNA methylation.

2.3 SNP genotyping and detection of DNA methylation

SNP genotyping was performed with the standard SNaPshot assay by Genesky Biotechnologies (Shanghai, China). The corresponding primers was first designed according to the sequences around the SNPs. Then, a fragment of DNA surrounding the SNPs was amplified by the polymerase chain reaction (PCR). The final product was separated by capillary electrophoresis with the ABI 3130XL Genetic Analyzer (Applied Biosystems Co. Ltd., CA, USA). GeneMapper 4.1 software was used to obtain the genotypes of the SNPs. To ensure the accuracy of genotyping, five percent of the samples were randomly selected and replicated.

For the methylation detection, DNA was first bisulfite conversed with the EZ DNA Methylation Gold™ Kit (Zymo Research Corporation, CA, USA). Then, the target region of the TH gene promoter, containing the CpG sites, was amplified with the corresponding primers (Table S4). Finally, the amplified products of the target fragments were analyzed using the Illumina Hiseq X Ten platform. The methylation level of the CpG site was defined as the percentage of methylated sites in all sequences containing this site. DNA methylation detection was also conducted by Genesky Biotechnologies.

2.4 Statistical analysis

PLINK (version 1.09) was used for the association analysis of TH gene variants and risk of heroin addiction, with age and gender as covariates. The association between TH gene variants and traits of heroin addiction was performed using Matrix eQTL (website at: http://www.bios.unc.edu/research/genomic_software/Matrix_eQTL) with the demographic information (age, gender, marital status, education, occupation, income per month and family relation) as covariates. For the comparison of DNA methylation between groups, student t test was used. Linear regression analysis with SPSS 22.0 was conducted for the association of genotypes of TH SNPs and level of DNA methylation. The significance threshold was set at adjusted P value < 0.05 after the Bonferroni correction.

3.1 Association between TH gene variants and susceptibility of heroin addiction

To determine the association of TH gene variants and risk of heroin addiction, two tag SNPs (rs10770140 and rs6356) were genotyped in 930 healthy controls and 801 patients with heroin addiction. Our results revealed that SNP rs6356 was associated with the susceptibility of heroin addiction. The distribution of genotypes of SNP rs6356 was different between groups (χ² = 8.636, P = 0.013). In the dominant inheritance model, the GG and GA genotype frequency was lower in the heroin addiction group (26.8%) than the healthy control group (33.0%) (χ² = 7.763, P = 0.005). For the minor allele frequency, the frequency of the G allele was lower in the patients with heroin addiction (14.8%) compared with the healthy controls (17.7%) (χ² = 5.660, P = 0.017). All the above significances survived after the Bonferroni correction (α = 0.05/2 = 0.025) (Fig. 1 and Table 1).

Table 1

Association of TH variants and risk of heroin addiction
SNP	Minor allele	Major allele	Model	Frequency in HA group	Frequency in control group	Chi-square	P value
rs10770140	A	G	Genotypic	2/102/697	5/119/806	0.890	0.641
	A	G	Trend	106/1496	129/1731	0.140	0.709
	A	G	Allelic	106/1496	129/1731	0.138	0.710
	A	G	Dominant	104/697	124/806	0.046	0.830
	A	G	Recessive	2/799	5/925	0.886	0.461
rs6356	G	A	Genotypic	22/193/586	24/282/621	8.636	0.013
	G	A	Trend	237/1365	330/1524	5.672	0.017
	G	A	Allelic	237/1365	330/1524	5.660	0.017
	G	A	Dominant	215/586	306/621	7.763	0.005
	G	A	Recessive	22/779	24/903	0.041	0.839
HA: heroin addiction.

3.2 Association between TH gene variants and traits of heroin addiction

To reveal the association between the genotypes of TH SNPs and traits of heroin addiction, five functional SNPs were genotyped in the heroin addiction group and linear regression analysis was conducted between the genotypes of SNPs and five traits of heroin addiction. According to our findings, only the polymorphism of rs10770140 was nominally associated with the age of onset for heroin use (Fig. 2, beta=-1.347, P = 0.028). Unfortunately, it did not remain significant after the Bonferroni correction (α = 0.05/5 = 0.010). The detailed results of the association of TH SNPs and traits of heroin addiction were shown in Table S5.

3.3 Differential methylation in the promoter region of the TH gene between the healthy control and heroin addiction groups

DNA methylation plays vital roles in substance addiction (Browne et al., 2020). To explore the potential mechanism of the association between TH gene variants and heroin addiction, we first detected and compared the methylation level in the promoter region of the TH gene between groups. Student’s t test revealed that the methylation level of CpG TH_15 was significantly higher in the heroin addiction group than the healthy control group (Fig. 3, t=-3.465, P < 0.001), even after the Bonferroni correction (Table 2, α = 0.05/15 = 0.003). However, the methylation level other CpG sites and the mean methylation level of the promoter region of the TH gene did not show difference between groups (all P > 0.05).

Table 2

Differential methylation in the promoter region of the TH gene between healthy control and HA groups
CpG site	Mean methylation level in control group	Mean methylation level in HA group	t	P value
TH_01	0.851	0.839	1.060	0.281
TH_02	0.970	0.972	-0.439	0.672
TH_03	0.920	0.917	0.412	0.716
TH_04	0.867	0.864	0.354	0.792
TH_05	0.934	0.937	-0.538	0.646
TH_06	0.884	0.887	-0.346	0.737
TH_07	0.579	0.571	1.401	0.278
TH_08	0.866	0.867	0.061	0.854
TH_09	0.968	0.967	0.896	0.465
TH_10	0.880	0.883	-0.964	0.340
TH_11	0.902	0.899	0.867	0.524
TH_12	0.956	0.955	0.466	0.803
TH_13	0.753	0.757	-0.354	0.580
TH_14	0.137	0.145	-2.383	0.014
TH_15	0.139	0.151	-3.465	< 0.001
TH_promoter_mean	0.735	0.759	-1.757	0.080
HA: heroin addiction.

3.4 Association of SNP rs6356 and methylation level of CpG TH_15

Previous studies suggest that mQTLs, the SNPs that have an association with the level of gene methylation, convey more vulnerability in human diseases including substance addiction than randomly selected SNPs (Lin et al., 2020; Min et al., 2021). Based on the results of differential methylation above, we then analyzed the association between the genotypes of rs6356 and the methylation level of CpG TH_15. Linear regression analysis demonstrated that there were no association between them (P > 0.05).

3.5 Expression quantitative trait locus of rs6356 in human brain regions

To further reveal the potential function of rs6356 in heroin addiction, we screened it in the GTEx database (website at: www.gtexportal.org). SNP rs6356 was found allele-specific associated with the expression level of the TH gene in human brain regions including hippocampus (P = 3.83E-04), caudate (P = 6.50E-03), nucleus accumbens (NAc, P = 8.22E-03), hypothalamus (P = 1.59E-02) and putamen (P = 1.91E-02). The subjects with AA genotype had the highest expression level of TH gene in the above brain regions, then came the GA and GG genotype subjects. The detailed outcome of eQTL of rs6356 was shown in Table 3.

Table 3

Expression quantitative trait locus of rs6356 in human brain regions.
SNP	eQTL in brain regions	Frequency of CC/CT/TT genotypes	P value
rs6356	Hippocampus	73/76/16	3.83E-04
	Caudate	82/91/21	6.50E-03
	Nucleus accumbens	84/95/23	8.22E-03
	Hypothalamus	64/86/20	1.59E-02
	Putamen	72/84/14	1.91E-02
eQTL: expression quantitative trait locus.

TH is involved in the rewarding effects of addictive substance (Fang et al., 2017; Vaillancourt et al., 2021). TH gene has long been an important candidate in genetic association studies in substance addiction. Further investigations of the potential mechanism in the correlation between TH gene variants and susceptibility and traits of opioid addiction are required. In the present study, we first determined the association between TH gene variants and susceptibility and traits of heroin addiction. The methylation level in the promoter region of the TH gene was detected and compared between heroin addiction and healthy control groups. Finally, mQTL and eQTL analysis was performed for the risk SNPs in heroin addiction to explore the potential mechanism or function of them in opioid addiction.

Long term addictive substance exposure induces neuronal adaptations including structural, functional and molecular changes in brain (Evangelou et al., 2021; Fernàndez-Castillo, Cabana-Domínguez, Corominas, & Cormand, 2021; Salery, Trifilieff, Caboche, & Vanhoutte, 2020; Snyder & Silberman, 2021). Epigenetic and gene expression alterations are essential molecular changes responsible for the neuronal adaptations that contribute to the development of substance addiction (Fernàndez-Castillo et al., 2021). Previous studies indicated that hypermethylation at several CpG sites in the TH gene is found in the postmortem NAc samples in the patients with cocaine addiction compared with the healthy controls (Vaillancourt et al., 2021). In accordance with the above findings, we observed that the methylation level of CpG TH_15 was higher in the heroin addiction group than the healthy control group. DNA methylation is one of the mechanisms that could inhibit the gene transcription and expression (Li, Gonzalez, Inzé, & Dubois, 2020). With potential role in regulating DNA methylation, mQTLs were believed to constitute more liability than random SNPs in diseases including heroin addiction (J. Zhang et al., 2021). Unfortunately, we failed to detect any association between the risk SNP rs6356 for heroin addiction and the methylation level of TH_15. Hence, other mechanisms rather than methylation patterns may underlie the association of rs6356 and risk of heroin addiction.

Our results demonstrated that SNP rs6356 is an eQTL that allele-specific correlated with the expression level of TH gene in the hippocampus and NAc. The A allele of rs6356 was associated with higher expression of TH gene in the above two brain regions. In addition, the A allele frequency in the patients with heroin addiction was found significantly higher than that in the healthy controls. This was consistent with previous findings in rodents that repeated morphine exposure caused upregulation of TH gene expression in the hippocampus (Fang et al., 2017) and locus coeruleus (Jalali Mashayekhi et al., 2018), two important brain regions in substance addiction. Hippocampus is engaged in the formation of pathological context memory in substance addiction (Z. Wang et al., 2020). NAc is responsible for the addictive substances-induced rewarding and reinforcement effects (Al-Hasani et al., 2021; Amaral et al., 2020). Increased dopamine release in brain regions of the mesocorticolimbic dopamine system, including hippocampus and NAc is shown in all kinds of addictive substance use (Morales & Pickel, 2012; Pinheiro et al., 2015). The increase of dopamine synthesis may be associated with the upregulation of TH expression in these brain regions. Thus, we speculate that the eQTL rs6356 is associated with heroin addiction by implicating the TH gene expression in brain regions including hippocampus and NAc.

Several limitations should be considered when interpreting the results of our study. First, we used candidate gene method to elucidate the role and potential function of the TH gene variants in heroin addiction. Genome-wide association studies with large amounts of participants have the highest resolution in identifying risk gene variants for addictive diseases. Second, the eQTL results were obtained from the GTEx database, we did not examine the expression level of TH gene in brain regions due to lack of postmortem brain samples. Third, functional studies should be conducted to verify the precise role of the TH gene variants in the development of heroin addiction.

In summary, we found the eQTL rs6356 was associated with the susceptibility of heroin addiction. CpG site TH_15 in the promoter region of the TH gene was hypermethylated in the heroin addiction group compared with the healthy control group. SNP rs6356 was allele-specific associated with the expression level of TH gene in mesocorticolimbic dopamine system brain regions including the hippocampus and NAc, but not the methylation level of CpG TH_15 in peripheral blood. Our findings suggest that the eQTL rs6356 is associated with opioid addiction, potentially by influencing the TH gene expression in the hippocampus and NAc. It will further extend the mechanism underlying the association of genetic variants and addictive disorders.

Data Availability Statement

The sequencing data of the methylation assaying has been deposited into Sequence Read Archive (SRA) under accession number PRJNA752473.

Ethics Approval and Consent to Participate

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.

Consent for Publication

The authors affirm that all participants provided informed consent for publication.

Availability of Data and Materials

All data and materials will be available upon reasonable request.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This work was supported by the Natural Science Foundation of Shaanxi Province (No. 2021JQ-065 and 2021JM-028) and the Young Talent Promotion Program of Shaanxi Science and Technology Association (No. 20200301).

Authors’ Contributions

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.

Acknowledgements

We thank all the participants for their contributions to the research.

Al-Hasani R, Gowrishankar R, Schmitz GP, Pedersen CE, Marcus DJ, Shirley SE, Bruchas MR (2021) Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement. Nat Neurosci 24(10):1414–1428. doi:10.1038/s41593-021-00898-2
Amaral IM, Lemos C, Cera I, Dechant G, Hofer A, Rawas E, R (2020) Involvement of cAMP-Dependent Protein Kinase in the Nucleus Accumbens in Cocaine Versus Social Interaction Reward. Int J Mol Sci 22(1). doi:10.3390/ijms22010345
Boundy VA, Gold SJ, Messer CJ, Chen J, Son JH, Joh TH, Nestler EJ (1998) Regulation of tyrosine hydroxylase promoter activity by chronic morphine in TH9.0-LacZ transgenic mice. J Neurosci 18(23):9989–9995. doi:10.1523/jneurosci.18-23-09989.1998
Browne CJ, Godino A, Salery M, Nestler EJ (2020) Epigenetic Mechanisms of Opioid Addiction. Biol Psychiatry 87(1):22–33. doi:10.1016/j.biopsych.2019.06.027
Chisholm A, Rizzo D, Fortin É, Moman V, Quteishat N, Romano A, Shalev U (2021) Assessing the Role of Corticothalamic and Thalamo-Accumbens Projections in the Augmentation of Heroin Seeking in Chronically Food-Restricted Rats. J Neurosci 41(2):354–365. doi:10.1523/jneurosci.2103-20.2020
Ciuculete DM, Voisin S, Kular L, Jonsson J, Rask-Andersen M, Mwinyi J, Schiöth HB (2020) meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes. Clin Epigenetics 12(1):99. doi:10.1186/s13148-020-00884-8
Degtyareva AO, Antontseva EV, Merkulova TI (2021) Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases. Int J Mol Sci 22(12). doi:10.3390/ijms22126454
Diamond I, Yao L (2015) From Ancient Chinese Medicine to a Novel Approach to Treat Cocaine Addiction. CNS Neurol Disord Drug Target 14(6):716–726. doi:10.2174/1871527314666150529144329
Evangelou E, Suzuki H, Bai W, Pazoki R, Gao H, Matthews PM, Elliott P (2021) Alcohol consumption in the general population is associated with structural changes in multiple organ systems. Elife 10. doi:10.7554/eLife.65325
Fang M, Li J, Zhu D, Luo C, Li C, Zhu C, Mo Z (2017) Effect of Sinomenine on the Morphine-Dependence and Related Neural Mechanisms in Mice. Neurochem Res 42(12):3587–3596. doi:10.1007/s11064-017-2407-5
Fernàndez-Castillo N, Cabana-Domínguez J, Corominas R, Cormand B (2021) Molecular genetics of cocaine use disorders in humans. Mol Psychiatry. doi:10.1038/s41380-021-01256-1
Gerra ML, Gerra MC, Tadonio L, Pellegrini P, Marchesi C, Mattfeld E, Ossola P (2021) Early parent-child interactions and substance use disorder: An attachment perspective on a biopsychosocial entanglement. Neurosci Biobehav Rev 131:560–580. doi:10.1016/j.neubiorev.2021.09.052
Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6(7):521–532. doi:10.1038/nrg1635
Huang CL, Chen PH, Lane HY, Ho IK, Chung CM (2021) Risk Assessment for Heroin Use and Craving Score Using Polygenic Risk Score. J Pers Med 11(4). doi:10.3390/jpm11040259
Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598. doi:10.1146/annurev.neuro.29.051605.113009
Jalali Mashayekhi F, Rasti M, Khoshdel Z, Owji AA (2018) Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine. Eur Addict Res 24(6):304–311. doi:10.1159/000495362
Li T, Gonzalez N, Inzé D, Dubois M (2020) Emerging Connections between Small RNAs and Phytohormones. Trends Plant Sci 25(9):912–929. doi:10.1016/j.tplants.2020.04.004
Lin H, Wang F, Rosato AJ, Farrer LA, Henderson DC, Zhang H (2020) Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases. Epigenomics 12(9):789–800. doi:10.2217/epi-2019-0270
Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, Relton CL (2021) Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation. Nat Genet 53(9):1311–1321. doi:10.1038/s41588-021-00923-x
Morales M, Pickel VM (2012) Insights to drug addiction derived from ultrastructural views of the mesocorticolimbic system. Ann N Y Acad Sci 1248:71–88. doi:10.1111/j.1749-6632.2011.06299.x
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(5):1011–1019. doi:10.1111/epi.14058
Perzel Mandell KA, Eagles NJ, Wilton R, Price AJ, Semick SA, Collado-Torres L, Jaffe AE (2021) Genome-wide sequencing-based identification of methylation quantitative trait loci and their role in schizophrenia risk. Nat Commun 12(1):5251. doi:10.1038/s41467-021-25517-3
Pinheiro CR, Oliveira E, Manhães AC, Fraga MC, Claudio-Neto S, Younes-Rapozo V, Lisboa PC (2015) Exposure to nicotine increases dopamine receptor content in the mesocorticolimbic pathway of rat dams and offspring during lactation. Pharmacol Biochem Behav 136:87–101. doi:10.1016/j.pbb.2015.07.012
Salery M, Trifilieff P, Caboche J, Vanhoutte P (2020) From Signaling Molecules to Circuits and Behaviors: Cell-Type-Specific Adaptations to Psychostimulant Exposure in the Striatum. Biol Psychiatry 87(11):944–953. doi:10.1016/j.biopsych.2019.11.001
Snyder AE, Silberman Y (2021) Corticotropin releasing factor and norepinephrine related circuitry changes in the bed nucleus of the stria terminalis in stress and alcohol and substance use disorders. Neuropharmacology 201:108814. doi:10.1016/j.neuropharm.2021.108814
Song W, Kossowsky J, Torous J, Chen CY, Huang H, Mukamal KJ, Wright A (2020) Genome-wide association analysis of opioid use disorder: A novel approach using clinical data. Drug Alcohol Depend 217:108276. doi:10.1016/j.drugalcdep.2020.108276
Stewart AF, Fulton SL, Maze I (2021) Epigenetics of Drug Addiction. Cold Spring Harbor Perspectives in Medicine 11(7). doi:10.1101/cshperspect.a040253
Vaillancourt K, Chen GG, Fiori L, Maussion G, Yerko V, Théroux JF, Turecki G (2021) Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum. iScience 24(10):103169. doi:10.1016/j.isci.2021.103169
Villicaña S, Bell JT (2021) Genetic impacts on DNA methylation: research findings and future perspectives. Genome Biol 22(1):127. doi:10.1186/s13059-021-02347-6
Walters CL, Kuo YC, Blendy JA (2003) Differential distribution of CREB in the mesolimbic dopamine reward pathway. J Neurochem 87(5):1237–1244. doi:10.1046/j.1471-4159.2003.02090.x
Wang X, Cheng W, Zhu J, Yin H, Chang S, Yue W, Yu H (2020) Integrating genome-wide association study and expression quantitative trait loci data identifies NEGR1 as a causal risk gene of major depression disorder. J Affect Disord 265:679–686. doi:10.1016/j.jad.2019.11.116
Wang Z, Jin T, Le Q, Liu C, Wang X, Wang F, Ma L (2020) Retrieval-Driven Hippocampal NPTX2 Plasticity Facilitates the Extinction of Cocaine-Associated Context Memory. Biol Psychiatry 87(11):979–991. doi:10.1016/j.biopsych.2019.10.009
Zhang H, Wang F, Kranzler HR, Yang C, Xu H, Wang Z, Gelernter J (2014) Identification of methylation quantitative trait loci (mQTLs) influencing promoter DNA methylation of alcohol dependence risk genes. Hum Genet 133(9):1093–1104. doi:10.1007/s00439-014-1452-2
Zhang J, Fan Y, Zhou J, Ma T, Gao K, Xu M, Zhu Y (2021) Methylation quantitative trait locus rs5326 is associated with susceptibility and effective dosage of methadone maintenance treatment for heroin use disorder. Psychopharmacology. doi:10.1007/s00213-021-05968-8
Zhao Y, He A, Zhu F, Ding M, Hao J, Fan Q, Ma X (2018) Integrating genome-wide association study and expression quantitative trait locus study identifies multiple genes and gene sets associated with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 81:50–54. doi:10.1016/j.pnpbp.2017.10.003
Zhou H, Rentsch CT, Cheng Z, Kember RL, Nunez YZ, Sherva RM, Gelernter J (2020) Association of OPRM1 Functional Coding Variant With Opioid Use Disorder: A Genome-Wide Association Study. JAMA Psychiatry 77(10):1072–1080. doi:10.1001/jamapsychiatry.2020.1206

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Editorial decision: Major Revision English Editing
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Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

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Journal Publication

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Abstract

Figures

1. Introduction

2. Materials And Methods

2.1 Study subjects

2.2 SNP selection and DNA extraction

2.3 SNP genotyping and detection of DNA methylation

2.4 Statistical analysis

3. Results

3.1 Association between TH gene variants and susceptibility of heroin addiction

3.2 Association between TH gene variants and traits of heroin addiction

3.4 Association of SNP rs6356 and methylation level of CpG TH_15

3.5 Expression quantitative trait locus of rs6356 in human brain regions

4. Discussion

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1