Background: Dopaminergic and opioid systems are involved in mediating drug reward and reinforcement of various types of substances including psychoactive compounds. Genes of both systems have been candidate for investiga- tion for associations with substance use disorder (SUD) in various populations. This study is the first study to deter - mine the allele frequency and the genetic association of the DRD2 rs1076560 SNP and OPRM1 rs1799971 SNP variants in clinically diagnosed patients with SUD from the United Arab Emirates (UAE). Methods: A cross-sectional case–control cohort that consisted of 512 male subjects was studied. Two hundred and fifty patients with SUD receiving treatment at the UAE National Rehabilitation Center were compared to 262 controls with no prior history of mental health and SUD. DNA from each subject was extracted and genotyped using the TaqMan SNP genotyping assay. Results: There were no significant associations observed for DRD2 rs1076560 SNP, OPRM1 rs1799971 SNP, and com- bined genotypes of both SNPs in the SUD group. Conclusion: Further research is required with refinements to the criteria of the clinical phenotypes. Genetic studies have to be expanded to include other variants of the gene, the interaction with other genes, and possible epigenetic relationships. Keywords: Substance use disorder, DRD2 gene, OPRM1 gene, rs1076560, rs1799971, UAE Background system for the variety of substances that are commonly The dopaminergic and opioid systems are part of a net - consumed. This dopaminergic system comprises an array work involved in rewarding response following the con- of dopamine receptors, transporters, and substance- sumption of opioids and other psychoactive substances metabolising enzymes. Members of the family of the [1, 2]. The dopamine system has been central to theo - dopamine receptor genes, DRD1, DRD2, DRD3, DRD4, ries in reward of substance use disorder (SUD) that has and DRD5, have been widely studied as risk factors for been debated for several decades . The consumption of SUD . The dopamine D2 receptor is a part of G pro - addictive substances stimulates the release of dopamine tein-coupled receptors (GPCRs) that is encoded by the into nucleus accumbens (NAc) elevating the dopamine DRD2 gene. It is located on chromosome 11q23, span- level to above basal levels . There are different mecha - ning a region of 65.56 kilobases and comprises 8 exons nisms of action and target molecules in the dopamine separated by 7 introns. During the splicing process of the DRD2 mRNA precursor, two alternative subtypes of the D2 receptors are formed: a 443 amino acid D2L or a 414 *Correspondence: email@example.com amino acid D2S form. The longer D2L form is more com - Center of Biotechnology, Khalifa University of Science, Technology mon . This 29 amino acid difference between the two and Research, PO Box 1227788, Abu Dhabi, United Arab Emirates Full list of author information is available at the end of the article isoforms does not appear to affect the pharmacological © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Alblooshi et al. Ann Gen Psychiatry (2018) 17:22 Page 2 of 7 properties of the dopamine D2 receptor. The D2L/S vari - with others not finding significant associations with SUD ation changes the localization of the third intracellular [23, 24]. loop of the receptor that interacts with the G coupled This study is the first study to report on the allele protein; hence, it affects the intracellular signalling mech - frequency for the rs1076560 SNP of DRD2 and the anism. The mechanisms of dopamine receptor signal rs1799971 SNP of OPRM1 in individuals with SUD from transduction and regulation are not only mediated via G the United Arab Emirates (UAE). This case–control study protein signalling, but also involve G protein independ- investigated the genetic association between the DRD2 ent signalling events . rs1076560 SNP and OPRM1 rs1799971 SNP and SUD Understanding the reward and the treatment responses in the UAE population. The allele frequencies of DRD2 highlight the necessity of reviewing the relation between rs1076560 SNP in the UAE population were compared the genetic variants of these dopaminergic genes and to other global populations. The allele frequencies of the SUD . Patriquin et al.  reviewed the correlation of OPRM1 rs1799971 SNP in this UAE study were com- dopaminergic genes to SUD. The genetic variants of pared with SUD cohorts in other Arab populations. DRD2 have been a focus of intense research to deter- mine their link to SUD. Two single-nucleotide polymor- Methods phisms (SNPs) of the DRD2 loci; rs2283265 in intron 5 Subject information and rs1076560 in intron 6 have been reported to be asso- A total of 250 male nationals of the UAE were recruited ciated with cocaine use . A DRD2 variant (rs1076560) from the National Rehabilitation Center (NRC) based has also been studied in various populations. Clark on the nation’s capital of Abu Dhabi. All participants et al.  reported the association between rs1076560 were previously diagnosed with SUD based on the and opioid use in African Americans (AA) (p = 0.03) DSM-5 criteria. Saliva samples were collected from each and European Americans (EA) (p = 0.02). These find - patient who had agreed to participate in this study, using ings introduced insights into the possible roles of these the DNA Oragene saliva kit (DNA Genotek, Ottawa, dopaminergic variants on SUD. However, the extent of Ontario, Canada). In addition, 262 male nationals of the genetic variations acting as a risk factor for SUD is still UAE with no prior history of SUD or mental illness were not understood. recruited as controls. These individuals were part of an The opioid receptor gene family has been extensively ongoing population study towards the establishment of studied to identify if there are any associations with the Emirates Family Registry (EFR) . The characteris - SUD. There three subtypes are μ, κ, and δ, encoded by tics of the cohort are summarised in Alblooshi et al.  the OPRM1, OPRK1, and OPRD1 genes, respectively. which includes socio-demographic data as well as the The product of the OPRM1 gene plays a role in facili - combination and types of substances that were used. The tating the analgesia and euphoria effects of opioids. The study was conducted in accordance with standards set G protein-coupled mu opioid receptor encoded by the by the World Medical Association of Helsinki . Spe- OPRM1 gene is a multiple trans-membrane protein that cifically, approval to study human subjects was obtained has a high affinity for endogenous and exogenous opioids from the NRC in Abu Dhabi. In addition, reciprocal . The OPRM1 gene consists of 9 exons which encode approval was obtained from the human ethic committee over 100 variants that produce between 19 and 39 splice at the University of Western Australia (RA/4/1/6715). forms of the protein . The rs1799971 (A118G) site is an SNP that is located in exon 1 of the OPRM1 gene. This Genotyping of single‑nucleotide polymorphism (SNP) variant encodes a missense change in OPRM1 at posi- Genomic DNA was isolated from the cells in human tion 40 resulting in a change from an asparagine to an saliva samples using the laboratory protocol for man- aspartate (Asn40Asp) in the extracellular domain of the ual extraction of DNA as recommended by Genoteck receptor. This substitution eliminates an N-glycosylation (Ottawa, Ontario, Canada). SNP genotyping was pre- site in the extracellular domain, which affects endog - formed using a TaqMan SNP genotyping assay on the enous opioid binding and receptor activity . The role viiA 7 (Applied Biosystems Inc. (ABI); Foster City, CA, of the rs1799971 in SUD remains in dispute [13, 14]. The USA). For quality control (QC) purposes, 10% of sam- effect of the variants of rs1799971 on different classes ples that were studied were randomly selected. These QC of substance has been extensively studied in various samples were genotyped at least twice. There was 100% populations [10, 11, 13, 15–20]. However, only two stud- concordance between the genotypes recorded for repli- ies [21, 22] have looked into rs1799971 variants in the cates from the same individual. The Hardy–Weinberg Arab population. Several studies have reported associa- equilibrium (HWE) was calculated for both the cases tions between A118G with different substances of use in and controls. No significant deviation from HWE was patients from different ethnic groups [10, 11, 13, 15–20], observed. Alblooshi et al. Ann Gen Psychiatry (2018) 17:22 Page 3 of 7 Identification and inclusion criteria of relevant studies determined using the STATA statistical software (College for comparison purposes Station, TX, USA). Life science journal articles containing information related to genotyping studies of the two SNPs of interest: Results DRD2 rs1076560 and OPRM1 rs1799971 were retrieved The allele frequencies of the DRD2 rs1076560 SNP in the from a search of electronic publication databases. Spe- patient and control groups were compared. The Minor cifically, articles in PubMed/MEDLINE (US National Allele Frequency (MAF) for DRD2 rs1076560 was the Library of Medicine), EMBASE (Elsevier B.V., Amster- “A” allele, with a frequency of 11.80% in the substance dam, The Netherlands), and ISI Web of Science (Thom - use group compared with 13.20% in the controls. Corre- son Reuters, New York, NY, USA) that were published spondingly, the “C” allele was 88.20% in cases and 86.80% to 15 March 2017 were retrieved. The search process in controls (Table 1). The χ allelic association between was set up to specifically identify case–control studies the DRD2 rs1076560 SNP and substance use was not sig- that examined associations between each SNP (DRD2 nificant in the UAE population that was studied [p = 0.52, rs1076560 and OPRM1 rs1799971) with different types of odds ratio (OR) = 0.88]. SUD in different populations or ethnic groups. Data that The results of this UAE study were compared with pub - were specifically extracted from these published studies lished data that included association studies between the for comparison included: (1) the number of cases and DRD2 rs1076560 SNP and the use of different substances controls; (2) the ethnicity of the study population; (3) (e.g., alcohol, cocaine, opioids, and poly-substances) in a the genotyping method used; (4) allele and genotype fre- number of different populations (e.g., Caucasians, Afri - quency data; (5) information related to Hardy–Weinberg can Americans, Asians, and Jordanian Arabs) (Table 1). equilibrium; and (6) the significance of the levels of asso - Six relevant publications matched the selection criteria ciations identified (p values and statistical tests). described in the “Methods” section. All the studies iden- tified were case versus control studies. Clark et al.  Statistical analysis studied a relatively large population of EA and AA (999 Allele and genotype frequencies in the cases and controls EA cases versus 656 EA controls and 278 AA cases versus from this study were calculated using the GenAlex pack- 750 AA controls) and showed that the DRD2 rs1076560 age (Peakall and Smouse 2006, 2012) and association was SNP was significantly associated with opioid use in both Table 1 Summary of the meta-analysis of the DRD2 rs1076560 in association with SUD in different populations Population Substance Phenotype Number Allele’s frequency p OR (95% CI) References (%) C A Caucasians Alcohol Case 171 79.00 21.00 0.14 1.34 (0.90–1.98)  Control 160 83.00 17.00 African Americans Opioid Case 278 88.00 12.00 0.03 1.43 (1.04–1.97)  Control 750 91.00 9.00 European Americans Case 999 83.00 17.00 0.02 1.27 (1.04–1.54) Control 656 86.00 14.00 African Americans Cocaine Case 45 94.00 6.00 0.53 0.66 (0.18–2.40)  Control 31 92.00 8.00 Caucasians Case 74 76.00 24.00 0.003 2.74 (1.38–5.45) Control 63 90.00 10.00 Japanese Alcohol Case 297 59.90 40.10 0.03 1.30 (1.02–1.66)  Control 425 66.00 34.00 Jordanian Arabs Poly-substance Case 220 84.30 15.70 0.03 1.53 (0.90–2.68)  Control 240 89.20 10.80 UAE Cohort Mixed Case 250 88.20 11.80 0.52** 0.88 (0.61–1.28) This study Control 262 86.80 13.20 CI confidence intervals, OR odds ratio ** p value of Armitage test using the status of mixed opioids (n = 250) versus no addiction (n = 262) Mixed: include single substance and poly-substance users Alblooshi et al. Ann Gen Psychiatry (2018) 17:22 Page 4 of 7 populations with p values of 0.02 and 0.03, respectively. combinations in both populations indicate significant The MAF of the DRD2 rs1076560 SNP was higher in EA association between the MAF “G allele” with SUD case group (17.0%) when compared to EA control group (p = 0.04, OR = 0.73). This enhanced the odd ratio value (14.0%) as well as in AA cases (12.0%) versus AA con- with no heterogeneity observed. The combined data were trols (9.0%) . Moyer et al.  studied cocaine users adjusted using Cochran–Mantel–Haenszel test that was in the same two ethnic groups (EA and AA) and showed close to the UAE cohort. that the DRD2 rs1076560 SNP was associated with The combined genotype frequencies for the DRD2 cocaine use in EA (p = 0.003, OR = 2.74), but not in AA rs1076560 SNP and OPRM1 rs1799971 SNP are summa- (p = 0.53, OR = 0.66). A polish study of European alcohol rised in Table 3. There were no significant associations users reported results that were not significant (p = 0.14, between the combined genotypes of both SNPs in cases OR = 1.34). In a study of Japanese patients, the risk allele (p = 0.88) and controls (p = 0.23). The combined geno - “A” of the DRD2 rs1076560 SNP was associated with type CC/AA was the highest in cases (55.6%) and controls alcohol use (p = 0.03, OR = 1.30) . To date, there has (50.8%). This was followed by the combined genotype only been one other study of patients of Middle Eastern CC/AG with similar representation in cases (22.0%) and descent. Al-Eitan et al.  found the DRD2 rs1076560 controls (22.9%). The combined genotype of the AC/GG SNP to be associated with poly-substance use in a Jorda- was not observed in any individuals in the case group. nian Arab population (p = 0.03, OR = 1.53). Whereas, this combined genotype was observed in 1.2% The OPRM1 rs1799971 SNP genotype frequencies of the control group. There were no cases or controls studied in two case–control studies of SUD in popu- subjects with the combined genotype, AA/GG. lations of Arab descent are summarised in Table 2. In this study, the MAF “G allele” was 15.4% in cases Discussion and 18.9% in controls. Overall, the association of the In the UAE cohort represented in this study, there was OPRM1 rs1799971 SNP was not significant in the UAE no significant genetic association between the DRD2 patients with SUD (p = 0.12, OR = 0.78). In comparison rs1076560 SNP (p = 0.52) and SUD. The MAF of the with an Egyptian Arab population, no significant asso - DRD2 rs1076560 SNP was higher in the controls (13.2%) ciation was reported between the OPRM1 rs1799971 when compared to the substance users (11.8%). This was SNP and Tramadol use (p = 0.54, OR = 0.73) with MAF similar to the observations made in an AA population “G allele” of 5.2% in cases and 7.0% in controls. Simple studied by Moyer et al. , where the MAF in cocaine Table 2 Distribution of the allele frequency of rs1799971 among Arab population Cohort Case Control p* OR (95% CI) p-hetero** AA AG GG Sum MAF (%) AA AG GG Sum MAF (%) UAE 175 73 2 250 15.4 171 83 8 262 18.9 0.12 0.78 (0.56–1.08) Egypt-Arabs 69 8 0 77 5.2 43 7 0 50 7.0 0.54 0.73 (0.26–2.07) Simple combination 244 81 2 327 13.0 214 90 8 312 17.0 0.04 0.73 (0.51–0.99) M-H adjusted 0.78 (0.57–1.06) 0.75 CI confidence intervals, MAF minor allele frequency, OR odds ratio * p value of Cochran–Armitage test using allelic model ** p-hetero: p value of heterogeneity of Breslow–Day of homogeneity test Cochran–Mantel–Haenszel test (CMH) is a test used in the analysis of stratified or matched categorical data Table 3 DRD2 rs1075650 and OPRM1 rs1799971 genotype combination among case–control of this cohort SNPs OPRM1 rs1799971 Genotype Case p Control p AA AG GG AA AG GG DRD2 rs1076560 genotype CC 55.60 22.00 0.80 0.88 50.76 22.90 1.91 0.23 AC 13.20 6.40 0.00 12.60 8.78 1.15 AA 1.20 0.80 0.00 1.91 0.00 0.00 Alblooshi et al. Ann Gen Psychiatry (2018) 17:22 Page 5 of 7 users (6.0%) was lower than in the control group at being a risk factor to different types of substances of 8.0%. In general, Moyer et al.  reported an associa- use including tobacco consumption , alcohol use tion between the DRD2 rs1076560 SNP and cocaine use, and sensitivity [13, 19, 34, 35], and opioid use [16, 36]. in EA but not the AA. The overall odds ratio of 1.94 in Other studies looked into inducing clinical symptoms population (n = 214) was attributed to an artefact aris- or mediating responses to therapeutic treatment [11, 17, ing from the small sample size that was studied . In a 37, 38]. The association between the OPRM1 rs1799971 more recent study, Clark et al.  replicated the Moyer SNP and SUD failed to reach statistical significance in et al.  study by increasing sample size. The DRD2 our study (p = 0.12) and in a previous study by Enabah rs1076560 SNP was found to be associated with opioid et al.  (p = 0.54). In addition, the MAF of the OPRM1 use disorder in the two populations examined in this rs1799971 SNP or “G allele” in our study (case = 15.4%, subsequent study (EA: p = 0.02, AA: p = 0.03), but not control = 18.9%) was distributed in a similar pattern to cocaine use (EA: p = 0.23, AA: p = 0.19). The MAF of Enabah et al.  (case = 5.2%, control = 7.0%), where the DRD2 rs1076560 SNP, the “A allele”, was found to be the MAF “G allele” was lower in cases than in the con- higher in the cases when compared to controls in both trols. However, by combining the two cohorts, as shown populations: EA at 17.0% versus 14.0%, respectively, and in Table 3, the increase in numbers resulted in a signifi - in AA at 12.0% versus 9.0%, respectively . cant association between the OPRM1 rs1799971 SNP The different association outcomes between the stud - and substance use. This suggests that a larger population ies may account for the differences in the substance of size in future studies is required. The OPRM1 rs1799971 use or the pattern of use in the cohorts that were studied. SNP association varies and appears to depend on the Table 1 summarises the type of substances in each study, study population and the nature of the substance of use. which included alcohol, opioid, cocaine, and poly-sub- For example, Chen et al.  examined the association stance use. Stratifying these studies based on the type or between the OPRM1 rs1799971 SNP and alcohol use dis- pattern of substance used is important to identify more order in two different populations (Asian and Caucasian) specific genetic risk variants . Iacono et al.  sug - in a meta-analysis study. They reported an association gested that specific substances influenced the nature of with the OPRM1 rs1799971 SNP in Asians (p ≤ 0.001) but the genes that are involved in the pharmacodynamics and not in Caucasian (p = 0.76). Other studies have reported pharmacokinetics of that substance [31, 32]. However, it a lack of association with alcohol use  and with is a challenge to stratify patients according to substance heroin and/or cocaine use [16, 23]. Since the OPRM1 of use, as often there is no single substance that is used by rs1799971 SNP has been widely studied in different patients and there are overlaps between the substances populations, we focused on compiling data based on the are used. Clark et al.  investigated associations with a Arab studies (Table 2). Another Arab study by Al-Eitan single substance. However, their study was plagued with et al.  investigated the role of OPRM1 variants includ- difficulties related to overlap between different types of ing the rs1799971 SNP on the outcomes of therapeutic the used substances . In addition, the differences in treatment for opioids. This association between OPRM1 the genetic architecture between populations could dic- rs1799971 SNP and the possibility of an increased chance tate whether a variant is associated or not (Table 1). For of relapse in patients undergoing Naltrexone treatment example, the association between DRD2 rs1076560 SNP for opioid use disorder in Jordanian patients was not sig- and alcohol use was statistically significant (p = 0.03, nificant (p = 0.55). The variability of the findings from the OR = 1.30) in a Japanese population . However, the range of studies conducted to date highlights some con- same SNP was not statistically significant in the Polish tribution by the OPRM1 rs1799971 SNP. However, the patients with alcohol use disorder (p = 0.14, OR = 1.30) variability in associations found to date requires further . Even though the findings of Malecka et al.  were study to understand the contribution of this SNP. not significant, the MAF “A allele” in the group of alcohol This study is the first to examine if there is any associa - users was higher in the cases (21.0%) than in the controls tion between combined genotypes of two genes (DRD2 (17.0%). In contrast, the MAF “A allele” in this UAE study rs1076560 SNP and OPRM1 rs1799971 SNP) and the sus- and the AA group in Moyer et al.  were opposite, ceptibility to SUD in patients of Arabian ancestry. There where the MAF “A allele” was higher in controls than in was no significant association found between the com - cases (Table 1). bined genotype frequencies of the two SNPs and disease This study found no significant genetic association in this case–control study (cases p = 0.88 and controls between the OPRM1 rs1799971 SNP (p = 0.12) with SUD p = 0.23). Although some studies support the combined among patients from the UAE population. The asso - effect of variants of these two genes (DRD2 and OPRM1), ciation between the OPRM1 rs1799971 SNP and vari- the exact mechanism remains elusive. This may suggest ous phenotypes of SUD has been studied and includes the involvement of other genetic variants within or in the Alblooshi et al. Ann Gen Psychiatry (2018) 17:22 Page 6 of 7 Abbreviations vicinity of the DRD2 and OPRM1 genes. For example, SUD: substance use disorder; UAE: United Arab Emirates; NRC: National Reha- Zhang et al.  examined 13 SNPs in the OPRM1 gene bilitation Center; EFR: Emirates Family Registry; DSM-5: Diagnostic and Statisti- using haplotype analysis in an association study involving cal Manual_5; SNP: single nucleotide polymorphism; QC: quality control; HWE: Hardy Weinberg equilibrium; AA: African American; EA: European American; substance use patients from two populations: European VNTR: variable number of tandem repeats. and Russian ancestries . They reported the involve - ment of the intronic variants of OPRM1 (rs511435, Authors’ contributions HA contributed to the design of the study, processing the samples, analysing rs534731, rs3823010, rs2075572, and rs609148) in the data, and preparing the manuscript. The NRC team, comprising of AEK, increasing risk to SUD. Some of these SNPs were located MS, and HAG, was involved in recruiting patients and accessing data for in linkage disequilibrium (LD) with OPRM1 rs1799971 patients. WO provided further assistance with statistical analysis. GH, HAS, and GT are supervisors of HA, who is a doctoral student at the University of SNP and others have been postulated to be involved in Western Australia. They contributed on all elements of the study. All authors transcription regulation or alternative gene splicing. The read and approved the final manuscript. findings in Zhang et al.  highlighted the limitation of Author details selecting a single SNP of a candidate gene to examine the School of Human Sciences, The University of Western Australia, Crawley, WA, genetic association with SUD. Australia. School of Psychiatry and Clinical Neurosciences, The University Interaction between the DRD2 and OPRM1 genes with of Western Australia, Crawley, WA, Australia. School of Medical and Health Sci- ences, Edith Cowan University, Perth, WA, Australia. Center of Biotechnology, other genes has been examined across different sub - Khalifa University of Science, Technology and Research, PO Box 1227788, Abu stances of use. For instance, Lechner et al.  examined Dhabi, United Arab Emirates. United Arab Emirates National Rehabilitation the combined effect of the OPRM1 rs1799971 SNP and Center, Abu Dhabi, United Arab Emirates. Faculty of Biomedical Engineering, Khalifa University of Science, Technology and Research, Abu Dhabi, United the DRD4 exon 3 VNTR variants on cigarette craving Arab Emirates. after alcohol consumption. The study reported that the presence of the G allele is associated with an increase in Acknowledgements We acknowledge the support of staff at Center of Biotechnology at Khalifa cigarette craving after alcohol consumption. However, no University of Science and Technology in Abu Dhabi, UAE. We also thank the significant association between to the exon 3 VNTR vari - nursing and clinical staff of the UAE National Rehabilitation Center (NRC) in ants of the DRD4 were found with the condition . In Abu Dhabi for their assistance in recruiting substance use patients to this study. Miss Alblooshi would like to acknowledge scholarship support from addition, Sullivan et al.  reported a gene–gene inter- UAE Higher Ministry of Education and Scientific Research that funded her action between the dopamine receptors gene (DRD2) and candidature as a Ph.D. student at the University of Western Australia. the dopamine transporter gene (DAT) in cocaine users. Competing interests The interaction between the regulatory variant of DRD2 The authors declare that they have no competing interests. (rs2283265) and dopamine transporters gene altered DAT protein activity, supporting the possibility that vari- Availability of data and materials The data sets used and analysed during the current study are available from ants being a risk factors for cocaine use . the corresponding author on reasonable request. Consent for publication All participants provided their consent for their de-identified data to be Conclusion published. This study provides insights into two major genes that are thought to be risk factors of substance use. Specifically, Ethics approval and consent to participate The approvals to involve human subjects in this study were obtained from the the DRD2 rs1076560 SNP and the OPRM1 rs1799971 NRC in Abu Dhabi and the University of Western Australia (RA/4/1/6715). SNP were studied in substance use patients from the UAE population. No significant association between Funding This research was funded by the UAE National Rehabilitation Center (NRC), the DRD2 rs1076560 SNP, the OPRM1 rs1799971 SNP, Abu Dhabi, UAE. and the combined genotype of the two SNPs and SUD was identified in this cohort. Nevertheless, future stud - Publisher’s Note ies must consider stratification of the disease phenotype Springer Nature remains neutral with regard to jurisdictional claims in pub- to assess possible association with DRD2 and OPRM1. lished maps and institutional affiliations. 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Annals of General Psychiatry – Springer Journals
Published: Jun 1, 2018
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