J Neural Transm DOI 10.1007/s00702-013-1029-6
PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE
The dopamine receptor D1 gene is associated with the length of interval between first heroin use and onset of dependence in Chinese Han heroin addicts Sufang Peng • Jiang Du • Haifeng Jiang • Yingmei Fu • Hanhui Chen • Haiming Sun • Dongxiang Wang • Shunying Yu • Min Zhao
Received: 20 October 2012 / Accepted: 17 April 2013 Springer-Verlag Wien 2013
Abstract Previous researches showed that the dopamine receptor D1 (DRD1) may play a critical role in drug dependence. This research aimed to determine whether DRD1 played a role in development of heroin dependence in Chinese heroin-dependent patients. 465 Chinese Han heroin-dependent subjects and 379 healthy controls were recruited in the Shanghai region. Five single-nucleotidepolymorphisms (SNPs) of the DRD1 gene were genotyped in all subjects. The results found that the frequencies of DRD1 SNP genotypes or haplotypes were not different between heroin-dependent patients and controls. Among heroin-dependent patients, subjects with rs5326CC and/or rs6882300AA genotypes develop to heroin-dependent more rapidly than those without rs5326CC and/or rs6882300AA genotypes. The results indicated that DRD1 gene polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han population, but it may be associated with the rapidity of heroin dependence development from first drug use. Keywords Heroin dependence DRD1 Genetic polymorphism Rapidity of dependence development
M. Zhao and S. Yu contributed equally to this work. S. Peng J. Du H. Jiang Y. Fu H. Chen H. Sun D. Wang S. Yu (&) M. Zhao (&) Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai 200030, China e-mail:
[email protected] M. Zhao e-mail:
[email protected]
Introduction Heroin addiction is a chronic relapsing disease characterized by compulsive drug seeking, drug abuse, tolerance and physical and psychological dependence. This complex disorder is a worldwide major public health problem. Although the underlying pathogenesis of heroin addiction is still unknown, numerous twin and family studies have shown that vulnerability to heroin addiction is influenced by interaction between multiple genetic and environmental factors (Vanyukov et al. 2007; Kreek et al. 2005; Li and Burmeister 2009). Other studies have implicated genetic predispositions providing the basic conditions for dependence on most classes of drugs (Tsuang et al. 1996). The dopamine pathway in the brain plays an important role in the pathogenesis of heroin addiction (Shalev et al. 2002). As dopamine receptors mediate the effects of dopamine, they are candidates for genetic study of opiate addiction. There are five dopamine receptors that have been classified into two groups: D1-like (D1 and D5) and D2-like (D2, D3, and D4). The gene for the dopamine receptor D1 (DRD1) is located at chromosome 5q35.1 and contains two exons separated by a small intron in the 5-untranslated region (UTR). DRD1 is critically involved in the locomotor activating effects of psychostimulant drugs (Ramos et al. 2004). Recent evidences also suggested that the DRD1 might play a determinant role in brain stimulation reward, reward prediction, and spatial learning (Tran et al. 2005). DRD1 was strongly associated with cue/ context-induced drug taking and reinforcement, which was supposed to have a major role in relapse (Williams and Goldman-Rakic 1995; Berglind et al. 2006; Bossert et al. 2009). The important role that DRD1 played in heroin dependence has also been confirmed. For example,
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Bossert’s research showed that DRD1 blockade in the shell of the nucleus accumbens decreased context-induced reinstatement of heroin seeking, whereas DRD1 blockade in the core of the nucleus accumbens decreased discrete cue-induced reinstatement (Bossert et al. 2007). Rowlett’s study indicated that administration of DRD1 agonists produced a leftward shift in the heroin dose–response function in rhesus monkeys trained to self-administer heroin (Rowlett et al. 2007). Nakajima’s study also demonstrated that DRD1 antagonist reduced the effect on heroin self-administration during maintenance (Nakajima and Wise 1987). However, Gerrits’s research did not find that DRD1 in the nucleus accumbens was involved in heroin reward (Gerrits et al. 1994). The majority of present genetic studies were focused on the role of D2-like dopamine receptor genes in opiate dependence (Gorwood et al. 2012). Several studies have reported DRD1 gene polymorphism was associated with other substance dependence such as alcohol (Batel et al. 2008), nicotine (Huang et al. 2008), nicotine metabolite ratio (Lee et al. 2012), and stimulants (Liu et al. 2006). Very few studies have examined the association between DRD1 gene and opiate addiction. Jacobs’s study (Jacobs et al. 2012) found polymorphisms of DRD1 gene to be associated with opiate addiction, despite significant differences in racial makeup of the separate samples. Another study (Levran et al. 2009) found DRD1 gene rs5326 to be associated with heroin dependence in African Americans; however, after correction for multiple testing, the associations indicated in that study were not significant. Considering the important role of DRD1 gene polymorphism in substance abuse, and existing evidence that DRD1 gene polymorphism associated with opiate dependence in different ethnic populations, we speculated that DRD1 gene polymorphism may associate with heroin dependence in Chinese Hans. In order to examine whether our hypothesis is correct or not, we analyzed the associations between genotypes and haplotypes of five tagging single-nucleotide polymorphisms (SNPs) in DRD1 gene and heroin dependence in Chinese Hans. No functional coding SNPs were found in DRD1 gene in previous study, but several noncoding functional SNPs, such as rs4532, rs5326 and rs686 in untranslated regions of DRD1 have been identified. They have been reported to be associated with nicotine addiction (Huang et al. 2008), heroin addiction (Levran et al. 2009), alcohol dependence (Batel et al. 2008) and schizophrenia (Zhu et al. 2011a). Therefore, we chose 5 SNPs located in the untranslated regions of DRD1 gene in this study. The clinical features of individual heroin dependence patients are quite different. In clinical settings, we have observed that individuals who have an earlier onset of drug use and the more rapid dependence development since their first drug use have greater severity of addiction and have poorer
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response to treatment (Behrendta et al. 2009; Sartor et al. 2009). These patients may be more susceptible to heroin addiction. The clinical features, such as onset of drug use, length of interval between first heroin use and onset of dependence may reflect the neurobiological response to heroin and have a genetic basis. Therefore, the association between the DRD1 gene SNP variants and clinical features were also assessed in the study. This study is important in that it will add new data for understanding the genetic basis of heroin dependence and provide useful information to individual intervention for heroin dependence.
Experimental procedures Ethics statement The research protocol was approved by the Ethics Committee of the Shanghai Mental Health Center, and every subject signed the informed consent form approved by the Institutional Review Board (IRB) at the Shanghai Mental Health Center. Research participants A total of 465 heroin-dependent patients (case group) from four drug rehabilitation centers in Shanghai were enrolled in this study. The case group included 222 men and 243 women and had a mean (SD) age of 37.44 (±7.84) years. All subjects were interviewed with the structured clinical interview for DSM disorders (SCID-I) by trained psychiatrists and met the criteria for heroin dependence according to the diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV). Subjects with other psychiatric diagnoses were excluded from this study. Blood and urine samples were obtained and assayed for genotypes and illicit drugs. Eligible subjects completed a self-report form that included basic demographic information (age, years of education, marital status, etc.) and consented to an interview to collect information on the history of drug use (age at onset of heroin use, frequency and amount of current daily use, times of previous drug treatment, etc.). The interval between first heroin use and onset of dependence was also included in this interview. The interval was defined as the duration from first use to the daily use and the appearance of withdrawal symptoms upon cessation of heroin use. The control group was recruited from the community and was composed of 379 healthy people. The control group included 214 men and 165 women and had a mean (SD) age of 31.56 (±8.63) years. The entire sample consisted of Han Chinese. There was no significant difference on gender and age distribution between case and control group (p [ 0.05).
The dopamine receptor D1 gene
SNPs selection and genotyping of DRD1 polymorphism
Results
DNA extraction was performed using a modified phenol/ chloroform method (Zhu et al. 2011b). Tagging SNPs for DRD1 were selected from the region of Chr5:174800642 …174813768 in the HapMap database for Han Chinese (see http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/ hapmap24_B36/). Tagging SNP was defined as having an r2 [ 0.8 and minor allele frequency (MAF) [ 0.15, and five tagging SNPs (rs4532, rs5326, rs2168631, rs6882300, rs267418) were selected (Fig. 1; Table 1). For DRD1 genetic polymorphism genotyping, TaqMan Genotyping Assay (Applied Biosystems, Foster City, California) was used on the ABI Prism 7900 sequence detection system. In order to calculate genotyping error, 5 % random DNA samples were genotyped twice for each SNP. The genotyping accuracy was 100 %.
Information on demographics and drug-using history of the subjects is summarized in Table 2. No deviation from Hardy–Weinberg equilibrium was found in the genotype distribution of any SNP in either the heroin-dependent group or the control group (p [ 0.05). DRD1 SNP genotypes and heroin dependence As shown in Table 3, there was no single SNP exhibiting significant differences in genotype frequencies between the heroin-dependent group and the control group (p [ 0.05). We examined LD structures within all genotype data (Fig. 2) and identified two haplotype-blocks, rs4532rs5326 and rs2168631-rs6882300-rs267418. However, no haplotype was associated with heroin dependence (p [ 0.05) (Table 4).
Statistical analyses Power and sample size calculations were computed with the G* power software (version 3.1.3, Franz Faul, Germany). The minimum of case sample size was estimated using frequencies observed in controls and heroin dependents with a = 5 % and b = 0.1. Online software (SHEsis; http://analysis.bio-x.cn/myAnalysis.php) (Shi and He 2005) was used to test Hardy–Weinberg equilibrium and linkage disequilibrium (LD). The frequencies of haplotype blocks were analyzed using the Haploview program v4.0 (Broad Institute, Cambridge, MA). Odds ratios (ORs) were used to measure the association between heroin dependence and DRD1 alleles or haplotype blocks. Unconditional logistic regression models were used to obtain maximum likelihood estimates of the ORs and their 95 % confidence intervals (CIs). Analysis of variance (ANOVA) and linear regression analysis were used to estimate the association between interval between first heroin use and onset of dependence of heroin, age at onset of drug use, duration of drug use, daily frequency of drug use and number of previous drug treatments and alleles. Because of the heterogeneity of variance of interval between first heroin use and onset of dependence of heroin, the data have been logarithmically transformed before ANOVA analyses. Statistical analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA). All tests were two-tailed, and the significance level was set at 0.05.
DRD1 SNP genotype and clinical features of heroin dependence In order to examine whether DRD1 gene was associated with clinical features of heroin dependence, ANOVA was used to analyze the differences of the age at onset of heroin use, the length of heroin use before developing to dependence, duration of heroin dependence, daily frequency of drug use and number of previous drug treatments among the five SNP genotypes in DRD1 gene. The results showed that subjects with the rs5326CC and/or rs6882300AA SNPs had shorter length of heroin use before developing to heroin dependent compared to individuals without the rs5326CC and/or rs6882300AA SNPs (p = 0.003 and 0.013 separately). Except the above-reported positive findings, there were no significant differences on the age at onset of heroin use, length of heroin use before developing to dependence, duration of heroin dependence, frequency of daily drug use and number of previous drug treatments among all DRD1 SNP genotypes (p [ 0.05) (Table 5).
Discussion To the best of our knowledge, this is the first study to evaluate the role of five SNPs in DRD1 gene on heroin dependence and the rapidity of heroin dependence
Fig. 1 Human DRD1 gene structure and location of five tagging SNPs
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S. Peng et al. Table 1 Location of five SNPs and MAF in different population Location
MAF in different population ASW
CEU
CHB
GIH
JPT
YRI 0.086
rs4532
Chr5:174802756
0.123
0.397
0.178
0.375
0.114
rs5326
Chr5:174802802
0.151
0.142
0.262
0.176
0.267
0.159
rs2168631
chr5:174808608
n/a
0.142
0.375
n/a
0.477
0.308
rs6882300
chr5:174809033
0.160
0.004
0.202
0.142
0.297
0.186
rs267418
chr5:174813251
0.226
0.389
0.423
0.307
0.436
0.142
Population descriptors: ASW African ancestry in Southwest USA; CEU CEPH (Utah residents with ancestry from northern and western Europe); CHB Han Chinese in Beijing, China; GIH Gujarati Indians in Houston, Texas; JPT Japanese in Tokyo, Japan; YRI Yoruba in Ibadan, Nigeria
Table 2 Demographic characteristics and drug use history for case group (n = 465)
Mean (SD) years of education (years) Primary school (1–6 years), n (%)
25 (5.4)
Middle school (7–12 years), n (%)
420 (90.3)
Junior college or above (more than 12 years), n (%) Marital status Married, n (%)
131 (28.2)
Divorced or separated, n (%)
93 (20.0)
Unmarried, n (%)
241 (51.8)
Mean age at onset of drug use (years) Interval between first heroin use and onset of dependence (months)
23.0 (6.2) 4.5 (8.8)
Mean duration of drug use (years)
14.4 (4.2)
Mean daily intake of heroin in grams
0.93 (0.5)
Mean daily frequency of drug use
3.0 (1.7)
Mean number of previous drug treatments (times)
6.7 (7.5)
development in Chinese Hans. As speculated, we found rs5326 and rs6882300 of DRD1 gene were associated with the length of interval between first heroin use and onset of dependence. However, not as expected, no association was found between SNPs or haplotypes in DRD1 gene and susceptibility to heroin dependence. The results are not consistent with other studies which found that DRD1 gene was associated with drug dependence. The most frequently studied polymorphisms in the DRD1 gene were rs4532 and rs5326, which are both located in the 50 -untranslated region (UTR). rs4532 has a transition from A to G, and rs5326 has a C transformed to T (Le Foll et al. 2009). rs6882300 is located in 30 -UTR and has a transition from A to T. Several studies have reported that DRD1 gene polymorphism is associated with alcohol dependence (Batel et al. 2008; Limosin et al. 2003a; Kim et al. 2007), nicotine dependence (Huang et al. 2008; Vink et al. 2006; Lyons et al. 1999), nicotine metabolite ratio (Lee et al. 2012), stimulant dependence (Liu et al. 2006) and a series of addictive behaviors (Comings et al. 1997). This may be due to DRD1 playing different roles in different drug dependence, or population difference. For heroin dependence, Levran’s study (Levran et al. 2009) found rs5326 associated with heroin dependence in an
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20 (4.3)
African-American sample, but all the associations indicated in that study were not significant after correction for multiple testing. So the researchers believed that it could have occurred by chance. However, a haplotype block consisting of rs686 (A)-rs5326 (A) was significantly associated with heroin addiction in that African-American sample (Levran et al. 2009). Jacobs’s study (Jacobs et al. 2012) found that rs686 was associated with opiate use (include heroin) in a complex sample, and when Caucasians and African Americans were examined separately, one significant association at two DRD1 SNPs (rs265975 and rs265973) was found in the Caucasian population, and another significant association at one DRD1 SNP (rs686) was found in the African-American population. In our study involving a Chinese Han sample, we found no significant association between SNPs or haplotype with heroin dependence. We did not detect rs686 in this study, but rs4532, which was located at 1450 bp upstream of rs686, was found to have strong LD with rs686 in HapMap database (r2 of 0.98) (http://hapmap.ncbi.nlm.nih.gov/cgiperl/gbrowse/hapmap24_B36/). Our research failed to prove the association of rs4532-rs5326 haplotype with heroin dependence, which may be attributable to the ethnic difference. Our results indicated that DRD1 gene
The dopamine receptor D1 gene Table 3 The distribution of genotype frequencies of DRD1 genotype SNP ID
Case (n = 369)
Control (n = 465)
V2
p value
1.785
0.410
0.881
0.348
OR (95 % CI)
rs4532 CC, n = 15 (1.8 %) CT, n = 222 (26.3 %)
9 (0.019)
6 (0.016)
114 (0.245)
108 (0.285)
TT, n = 607 (71.9 %)
342 (0.735)
265 (0.699)
C, n = 252 (14.9 %)
132 (0.142)
120 (0.158)
T, n = 1436 (85.1 %)
798 (0.85)
638 (0.842)
0.879 (0.672–1.150)
rs5326 CC, n = 503 (59.6 %)
272 (0.585)
231 (0.609)
CT, n = 295 (35.0 %)
171 (0.368)
124 (0.327)
TT, n = 46 (5.5 %)
22 (0.047)
24 (0.063)
2.177
0.337
715 (0.769) 215 (0.231)
586 (0.773) 172 (0.227)
0.043
0.836
AA, n = 132 (15.6 %)
82 (0.176)
50 (0.132)
AG, n = 406 (48.1 %)
210 (0.452)
196 (0.517)
GG, n = 306 (36.3 %)
173 (0.372)
133 (0.351)
4.755
0.093
A, n = 670 (39.7 %)
374 (0.402)
296 (0.391)
G, n = 1018 (60.3 %)
556 (0.598)
462 (0.609)
0.237
0.627
1.370
0.504
0.541
0.462
0.053
0.974
0.040
0.842
C, n = 1301 (77.1 %) T, n = 387 (22.9 %)
0.976 (0.777–1.226)
rs2168631
1.050 (0.863–1.277)
rs6882300 AA, n = 508 (60.2 %)
287 (0.617)
221 (0.583)
AT, n = 305 (36.1 %)
160 (0.344)
145 (0.383)
TT, n = 31 (3.7 %)
18 (0.039)
13 (0.034)
A, n = 1321 (78.3 %)
734 (0.789)
587 (0.774)
T, n = 367 (21.7 %)
196 (0.211)
171 (0.226)
1.090 (0.865–1.376)
rs267418 CC, n = 152 (18.0 %)
85 (0.183)
67 (0.177)
CG, n = 422 (50.0 %) GG, n = 270 (32.0 %)
232 (0.499) 148 (0.318)
190 (0.501) 122 (0.322)
C, n = 726 (43.0 %)
402 (0.432)
324 (0.427)
G, n = 962 (57.0 %)
528 (0.568)
434 (0.573)
1.020 (0.840–1.238)
Fig. 2 Linkage disequilibrium (LD) statistics between all pairs of markers. a LD quantified by values of D’ is indicated in percent in each box. Darker red indicates D’ [0.8, when D’ = 1.0, there is no number in the squares. b r2 is indicated in percent in each box, and the red squares indicating higher linkage between respective alleles
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S. Peng et al. Table 4 DRD1 haplotype analysis between the case and control group
Case (%)
Control (%)
v2
p
OR (95 %CI)
rs4532 ? rs5326 CC
131.93 (0.142)
119.92 (0.158)
0.879
0.348
0.880 (0.673–1.150)
TC
583.07 (0.627)
466.08 (0.615)
0.258
0.611
1.053 (0.864–1.283)
TT
214.94 (0.231)
171.92 (0.227)
0.044
0.835
1.025 (0.815–1.287)
rs2168631 ? rs6882300 ? rs267418 AAG
180.45 (0.194)
144.44 (0.191)
0.163
0.686
0.951 (0.745–1.214)
ATG
193.54 (0.208)
136.42 (0.180)
0.755
0.385
1.115 (0.873–1.424)
GAC
400.77 (0.431)
297.81 (0.393)
0.344
0.558
1.061 (0.871–1.293)
GAG
152.77 (0.164)
134.41 (0.177)
1.579
0.210
0.849 (0.657–1.096)
Table 5 Clinical features by different DRD1 genotypes in heroin-dependent patients
rs4532
The length of heroin dependence development (lgmonths)
Age at onset of drug use (years)
Duration of drug use (years)
Daily frequency of drug use (times per day)
Number of previous drug treatments
TT (n = 342)
0.364 (0.488)
23.08 (6.407)
14.366 (4.205)
3.960 (1.683)
6.420 (7.255)
CC and CT (n = 123)
0.291 (0.441)
22.73 (5.456)
14.675 (4.219)
3.940 (1.741)
7.640 (8.248)
2.088 0.149
0.296 0.587
0.481 0.489
0.006 0.964
2.305 0.126
CC (n = 272)
0.290 (0.460)*
22.97 (6.181)
14.390 (4.056)
4.020 (1.767)
6.510 (7.284)
TT and CT (n = 193)
0.422 (0.489)
23.02 (6.161)
14.529 (4.499)
3.860 (1.5953)
7.070 (7.894)
8.689
0.005
0.121
0.989
0.609
F p rs5326 F p rs2168631
0.003
0.943
0.728
0.320
0.436
GG (n = 173)
0.319 (0.435)
23.27 (6.083)
14.145 (4.007)
3.980 (1.764)
6.410 (6.522)
AA and AG (n = 292)
0.359 (0.499)
22.83 (6.219)
14.627 (4.371)
3.940 (1.658)
6.940 (8.093)
0.753
0.569
1.405
0.058
0.546
0.386
0.451
0.236
0.810
0.460
0.301 (0.466)*
22.98 (6.076)
14.293 (4.021)
4.05 (1.777)
6.620 (7.290)
F p rs6882300
AA (n = 287) TT and AT (n = 178)
F p
0.414 (0.486)
23.02 (6.327)
14.697 (4.576)
3.790 (21.549)
6.940 (7.947)
6.216
0.005
0.997
2.651
0.188
0.013
0.944
0.319
0.104
0.664
CC and CG (n = 314)
0.333 (0.464)
22.94 (6.297)
14.360 (3.996)
3.930 (1.678)
6.670 (7.410)
GG (n = 148) F
0.368 (0.503) 0.519
23.11 (5.895) 0.078
14.635 (4.733) 0.425
4.000 (1.740) 0.176
6.890 (7.837) 0.083
p
0.472
0.781
0.515
0.675
0.774
rs267418
* Bold values indicate p \ 0.05
polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han population. The most intriguing finding of our study was the association of rs5326 and rs6882300 with the length of the interval between first heroin use and onset of dependence. Participants who carried rs5326CC and/or rs6882300AA genotypes became heroin dependent more rapidly than those without rs5326CC and/or rs6882300AA genotypes. The results suggested that people who carried the rs5326CC and/or rs6882300AA genotype were more sensitive to heroin dependence. Both for the rs5326 and
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rs6882300, T allele was the minor allele (22.9 and 21.7 % separately), in spite of no association with susceptibility of heroin dependence in Chinese Han was found, T allele was associated with an increased length of interval between first heroin use and onset of dependence in a dominant model. Levran’s study (Levran et al. 2009) has found T allele of rs5326 associated with heroin dependence in African Americans, but there was no consistent result in Chinese Han. We speculate that T allele in rs5326 and rs6882300 might play a protective role in heroin dependence in Chinese Han. However, we did not find rs5326 or rs6882300 genotypes associated with other clinical features such as
The dopamine receptor D1 gene
age at onset of drug use, duration of drug use, daily frequency of drug use and number of previous drug treatments. This indicates that the association between rs5326 or rs6882300 genotypes and the rapidity of heroin dependence development is not due to other confounded factors. Because DRD1 is involved in the locomotor effects and rewarding effects of heroin abuse (Kalivas and Stewart 1991), and also strongly associated with cue/contextinduced heroin taking, maintenance and reinforcement (Nakajima 1989; Williams and Goldman-Rakic 1995; Berglind et al. 2006), we speculate that the DRD1 rs5326 or rs6882300 variant may impact the function of DRD1 and subsequently play a role in the rapidity of heroin dependence development. Our clinical observation found that individuals who quickly developed to dependent state usually were more severe addicts and usually had poor response to treatment. Patients with rs5326CC and/or rs6882300 genotypes may have more severe addiction and poor treatment outcome. From the findings of the study, we may infer that the rapidity of heroin-dependent development have genetic predispositions. However, the mechanism underlying their association remains unclear. Other factors, for example, personality characteristics may also play a role in this relationship, since previous research has shown that personality may relate with addiction susceptibility (Huang et al. 2008; Limosin et al. 2003b; Vink et al. 2006; Gerra et al. 2008). Future study is needed to elucidate other factors which mediate the association. Several limitations of our research should be mentioned. First, the length of the interval between first heroin use and onset of dependence was based on self-report, and the validity may be compromised by recall bias or mistakes. Second, the control groups are ‘‘inadequate’’ controls who never use drugs or susceptible to drug dependence, and may not comparable to the patients. In spite of these limitations, the study provided some new insight into the genetic mechanism of susceptibility to heroin dependence. For the first time, we found DRD1 gene polymorphism play a role in the rapidity of heroin dependence development, and these findings have clinical implications for individual diagnoses and intervention. Further study with improved design, for example, including objective measurements to assess the severity of addiction, and choosing more adequate controls by personality test or imposing more stringent requirements on the control group are needed to confirm the results of this study. Conclusion In conclusion, the present results suggest that DRD1 gene polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han
population, but it may be associated with the rapidity of heroin dependence development from first drug use. Acknowledgments This study was supported by a grant from the Chinese National Basic Science Foundation (30971048, 81271468, 81130020), Shanghai One Hundred Talent Project (XBR2011015). The authors wish to thank Professor Walter Ling (Integrated Substance Abuse Programs, Department Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA) for his help on language improvement. Conflict of interest of interest.
The authors declare that they have no conflict
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