Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples

PAID-08379; No of Pages 5 Personality and Individual Differences xxx (2017) xxx–xxx

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Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples T. Plieger a,⁎, A. Felten a, M. Melchers a, S. Markett a,b, C. Montag c,d, M. Reuter a,b a

Department of Psychology, Laboratory of Neurogenetics, University of Bonn, Germany Center for Economics & Neuroscience, University of Bonn, Germany Institute of Psychology and Education, Ulm University, Ulm, Germany d Key Laboratory for NeuroInformation/Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China b c

a r t i c l e

i n f o

Article history: Received 2 December 2016 Received in revised form 24 May 2017 Accepted 31 May 2017 Available online xxxx Keywords: Biosocial personality theory Reward dependence Dopamine DBH rs1611115

a b s t r a c t Cloninger's biosocial personality theory postulates a biological basis for the basic temperaments. With respect to reward dependence (RD) characterized by a tendency to sustain rewarding behaviors and to prefer behaviors previously associated with reward, he hypothesized low noradrenaline (NA) levels. Previous endocrine and genetic association studies have supported this hypothesis. The aim of the present study was to test for an association between the functional single nucleotide polymorphism rs1611115 (C-970T) on the dopamine-β-hydroxylase (DBH) gene and RD. DBH is an enzyme crucial for the synthesis of NA by catalyzing the oxidative hydroxylation of dopamine to NA. In two independent samples (N = 1144 and N = 826) of healthy participants we found significant genotype effects (p ≤ 0.0001 and p ≤ 0.05). Carriers of the C allele had significant higher RD scores than carriers homozygous for the T allele. Although the general RD–NA hypothesis was corroborated, the directionality of the observed effect was antithetical. Based on previous functionality studies reporting low enzymatic activity related to the TT genotype, present results indicate high NA levels in subjects scoring high on RD (in contrast to Cloninger's thesis). Future studies have to analyze how DBH activity and NA levels are dependent on the availability of dopamine. © 2017 Elsevier Ltd. All rights reserved.

1. Introduction Personality traits have been shown to be highly heritable and relatively stable over the life-span (Bouchard, Lykken, McGue, Segal, & Tellegen, 1990; Roberts & DelVecchio, 2000). Inspired by biologically oriented theories on personality, psychiatry research has acknowledged the predictive power of personality traits for psychopathological disorders (Grabe, Spitzer, & Freyberger, 2004). The basic idea is that phenotypic variability in healthy subjects and patients suffering from mental illness have the same biological underpinnings (Montag, Jurkiewicz, & Reuter, 2012; Montag & Reuter, 2014). This continuum model covers the full range from the normal to psychopathology and has been supported by numerous studies (e. g. Van Os, Linscott, Myin-Germeys, Delespaul, & Krabbendam, 2009). The biosocial personality theory of psychiatrist Robert Cloninger was most influential for paving the way for the idea that personality traits can predispose for psychopathology (Cloninger, Svrakic, & Przybeck, 1993). Cloninger suggested that ⁎ Corresponding author at: University of Bonn, Department of Psychology, Center of Economics & Neuroscience, Laboratory of Neurogenetics, Kaiser-Karl-Ring 9, D-53111 Bonn, Germany. E-mail address: [email protected] (T. Plieger).

personality can be best described by four temperaments (novelty seeking, harm avoidance, reward dependence, and persistence) and three character dimensions (self-directedness, cooperativeness and self-transcendence). Temperaments should have a strong genetic basis whereas character dimensions are influenced by learning mechanisms in social contexts. With respect to the temperaments he made clear statements on their biological basis (Cloninger, 1987a). Of relevance for the present study, reward dependence (RD) is thought to be associated with low activity of the noradrenergic neurotransmitter system. RD, also called the behavioral maintenance system, is characterized by resistance to extinction of previously rewarded behavior (Cloninger, 1987b). Subjects scoring high on RD are marked by sentimentality, attachment and dependence (especially on the opinion of others). Biochemical studies supported the hypothesis of a link between RD and the noradrenergic system. For example, Curtin et al. (1997) reported that monoamine levels explained 44% of the variance of RD in healthy male participants. RD correlated significantly with urinary epinephrine and 3-methoxy-4hydroxyphenylglycol (MHPG; a metabolite of epinephrine and norepinephrine) levels (r = 0.51 and r = 0.50, respectively). Support for Cloninger's personality theory comes also from molecular genetic studies. Given the high heritability of personality it is plausible that gene variants explain variance in RD. In contrast to endocrine

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Please cite this article as: Plieger, T., et al., Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples, Personality and Individual Differences (2017), http://dx.doi.org/10.1016/j.paid.2017.05.050

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T. Plieger et al. / Personality and Individual Differences xxx (2017) xxx–xxx

studies, which relate hormone levels mostly in the periphery (blood, saliva, urine) to personality, genetic studies investigating neurotransmitter relevant polymorphisms with putative effects on central nervous gene expression represent a more direct approach. In a small healthy Korean sample (N = 115) the T-182C polymorphism of the norepinephrine transporter was associated with RD (Ham, Choi, Lee, Kang, & Lee, 2005). Yamano et al. (2008) found an association between RD and a single nucleotide polymorphism (SNP) on the phenylethanolamine N-methyltransferase (PNMT) gene (rs3764351) in a sample of N = 85 Japanese healthy females. PNMT converts norepinephrine (NE) to epinephrine and therefore has an effect on noradrenaline availability. In a further study from Japan on N = 324 healthy participants, a VNTR polymorphism on the MAO-A gene was associated with novelty seeking and RD (Shiraishi et al., 2006). MAO-A catabolizes the monoamines noradrenaline and serotonin (5-HT). Therefore, MAOA influences besides PNMT noradrenaline levels. However, in a sample of N = 370 Chinese female participants the positive association between the MAO-A VNTR and RD could not be replicated (Yu et al., 2005). Given that personality traits are polygenetically determined, there must be numerous gene variants involved in the expression of personality (see Montag & Reuter, 2014). If Cloninger's theory is valid than all genetic factors influencing the activity of the noradrenergic system should be potential candidate genes for disentangling the molecular genetic basis of RD. Besides the genes coding for PNMT, MAO-A and catechol-O-methyltransferase (COMT; catabolizing NE and dopamine (DA) in the synaptic cleft), the dopamine-β-hydroxylase (DBH) gene deserves testing for an association with RD. DBH metabolizes dopamine to noradrenaline and therefore has an influence on NE availability. Polymorphisms on the DBH gene have been successfully associated with various phenotypes. Most interestingly, Punchaichira, Prasad, Deshpande, and Thelma (2016) could show that the SNP rs1611115 (C-970T), located in the distal promoter region of the DBH gene, is functional, i.e. impacts the enzyme quantity of dopamine-β-hydroxylase. This finding corroborates a previous study showing that rs1611115 could explain up to 50% of the variance in DBH activity (Zabetian et al., 2001). A clear allele load effect could be demonstrated in both studies with highest enzymatic activity in carriers of the CC genotype, intermediate activity in heterozygous CT carriers and lowest activity in carriers homozygous for the T allele. Genetic expression analyses supported the endocrine studies. DBH gene expression rates were also dependent of rs1611115 (C-970T) and again the C allele is associated with significantly higher activity than the T allele (Barrie et al., 2014; Chen et al., 2010). In sum, lower enzyme activity in T-allele carriers might be associated with lower NE levels. There is plenty of evidence that rs1611115 effects phenotypes related to catecholaminergic activity. With respect to drug addiction carriers of the TT genotype show increased severity of heroin use (Xie et al., 2013) and poorer cocaine treatment outcomes (Kosten et al., 2013). Moreover, disulfiram, a pharmacological drug influencing DBH activity, is successfully applied in the treatment of substance and non-substance addictions (Carroll et al., 2004; Skinner, Lahmek, Pham, & Aubin, 2014). Recently, Yang, Balodis, Lacadie, Xu, and Potenza (2016) demonstrated that rs1611115 influences brain activity in the amygdala, the ventromedial prefrontal cortex, and striatal areas in response to emotional and motivational cues in both pathological gamblers as well as in healthy controls. More precisely, T allele carriers showed a reduced BOLD response to gambling, drug, or sad cues as compared to participants homozygous for the C allele (genotype CC). Noteworthy, rs1611115 has been also successfully associated with personality (Hess et al., 2009): Carriers of the TT genotype showed higher neuroticism and novelty seeking (NS) scores as compared to subjects carrying at least one C allele in a sample of N = 637 patients with personality disorder. Although the authors had also included N = 387 healthy controls in order to compare the genotype frequencies between patients and controls (no effect), the influence of rs1611115 on personality was not reported for the control sample.

Given the fact that most criticism on genetic association studies is the lack of replicability (Hirschhorn, Lohmueller, Byrne, & Hirschhorn, 2002), the aim of the present study is to investigate the influence of the DBH polymorphism rs1611115 (C-970T) on RD in two independent samples of healthy participants. 2. Methods 2.1. Participants The total sample consisted of N = 1970 healthy volunteers who are members of one of our two bigger databases (Sample1: N = 1144, n = 338 males and n = 806 females; Sample2: N = 826, n = 322 males and n = 504 = females). Sample1 is a gene data bank of healthy participants who have registered to support studies on the biological basis of affective and cognitive behavior. This data bank predominately consists of young participants, mostly students of our Institute. Participants of Sample2 were recruited throughout Germany (mostly in companies) to serve as healthy controls for inpatients of psychiatric hospitals suffering from burnout syndrome and/or depression (for a detailed description see Melchers, Plieger, Meermann, & Reuter, 2015; Plieger, Melchers, Montag, Meermann, & Reuter, 2015). Therefore, Sample2 participants are older on average (M: 40.22, SD = 11.52) than Sample1 participants (M: 25.09, SD = 8.03) and more representative for the German population. 2.2. Personality assessment Cloninger's ‘Temperament and Character Inventory (TCI)’ was administered in order to assess RD (Cloninger et al., 1993). The self-report inventory consists of 240 dichotomous variables and measures the four temperaments ‘novelty seeking’, ‘harm avoidance’, ‘reward dependence’ and ‘persistence’ and the three characters ‘cooperativeness’, ‘self-directedness’ and ‘self-transcendence’. 2.3. Genetic analyses DNA was extracted from buccal cells. Automated purification of genomic DNA was conducted by means of the MagNA Pure® LC system using a commercial extraction kit (MagNA Pure LC DNA isolation kit; Roche Diagnostics, Mannheim, Germany). We genotyped for the DBH-gene SNP rs1611115 (C-970T) on chromosome 9q34.2 by means of MALDI-TOF mass spectrometry using the MassARRAY-4 system (Agena Bioscience; Hamburg, Germany). 2.4. Statistical analyses We calculated ANCOVA models to test the association between rs1611115 (C-970T) and RD in both samples independently. The genotype and gender constituted the independent variables, RD sum scores inferred from the TCI the dependent variable, and age of the participants was entered as covariate. First, ANCOVAs on the genotype were conducted with the three levels TT, CT and CC. Second, based on the genotype results, genotypes were grouped on the allele level contrasting allele carriers (genotypes CC and CT) with carriers homozygous for the (genotype TT). 3. Results 3.1. Descriptive statistics of both samples under investigation Gender and genotype distributions for both samples are presented in Tables 1 and 2. The genotype frequencies of both samples were in Hardy-Weinberg-Equilibrium (Sample2: Chi2 = 0.019, DF = 1, p = 0.890; Sample1: Chi2 = 0.007, DF = 1, p = 0.933).

Please cite this article as: Plieger, T., et al., Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples, Personality and Individual Differences (2017), http://dx.doi.org/10.1016/j.paid.2017.05.050

T. Plieger et al. / Personality and Individual Differences xxx (2017) xxx–xxx

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Table 1 The association between DBH rs1611115 (C-970T) and RD. ANCOVA results and descriptive statistics. Sample2 (healthy controls N = 826) from the Burnout Project.

Men

Women

Total

Age Gender rs1611115 Gender × rs1611115 rs1611115_C

n

M

SEM

TT CT CC TT CT CC TT CT CC

23 104 195 20 190 294 43 294 489

12.414 15.052 14.786 14.615 16.493 16.323 13.514 15.773 15.554

0.762 0.359 0.261 0.816 0.265 0.213 0.558 0.223 0.169

F 6.70 17.16 7.12 0.20 13.66

df (1,819) (1,819) (2,819) (2,819) (1,821)

p 0.010 0.000038 0.000857 0.819 0.000233

eta2 0.008 0.021 0.017 0.000 0.016

3.2. The influence of age and gender on RD In both samples we see effects of gender and age on RD. Women exhibit significantly higher RD scores than men (see Tables 1 and 2) and age correlates negatively with RD (Sample2: r = − 0.099, p = 0.004; Sample1: r = − 0.256, p ≤ 0.0001); i.e. younger subjects tend to have higher RD scores. Therefore, the influence of age and gender was controlled in ensuing ANCOVA models. 3.3. Influence of rs1611115 on RD In Sample2 there was a significant main-effect of rs1611115 genotype on RD (F(2,819) = 7.12, p = 0.000857, eta2 = 0.017). This genotype effect could be replicated in Sample1 (F(2,1137) = 3.19, p = 0.041, eta2 = 0.006; see Fig. 1). In both samples there was no interaction effect gender by rs1611115. In order to avoid reporting spurious associations and to obtain indicators for discriminant validity we also tested for potential effects of rs1611115 on the remaining six temperament/character dimensions of the TCI. In the larger Sample1 there was no other significant effect of rs1611115 on personality. In Sample2 there was also a weak effect on cooperativeness (p = 0.031) that was not replicated in Sample1 and that does not hold for Bonferroni correction. 4. Discussion The biosocial personality theory of Robert Cloninger (1986, 1987a, 1987b) has been proven to be of importance in the prediction of diverse Table 2 The association between DBH rs1611115 (C-970T) and RD in Sample1 (N = 1144 healthy participants). ANCOVA results and descriptive statistics.

Men

Women

Total

Age Gender rs1611115 Gender × rs1611115 rs1611115_C

n

M

SEM

TT CT CC TT CT CC TT CT CC

13 111 214 43 281 482 56 392 696

12.751 14.691 15.078 16.973 17.575 17.530 14.861 16.130 16.302

0.977 0.335 0.243 0.538 0.213 0.163 0.557 0.198 0.145

F 47.88 60.93 3.19 1.40 5.91

df (1,1137) (1,1137) (2,1137) (2,1137) (1,1139)

p b0.0001 b0.0001 0.041 0.284 0.015

eta2 0.040 0.051 0.006 0.002 0.005

Fig. 1. The association between DBH rs1611115 (C-970T) and RD. ANCOVA results and descriptive statistics. Left: Data of Sample2 (healthy controls N = 826). Right: Data of Sample1 (healthy participants N = 1144). In Sample2 there was a significant maineffect of rs1611115 genotype on RD (F(2,819) = 7.12, p = 0.000857, eta2 = 0.017). This genotype effect could be replicated in Sample1 (F(2,1137) = 3.19, p = 0.041, eta2 = 0.006). For further statistics please see Tables 1 and 2.

psychopathologies (Mulder, Joyce, Sullivan, Bulik, & Carter, 1999) and therapy outcomes (Cloninger, Svrakic, & Przybeck, 2006; Terock et al., 2015), and has yielded evidence that behavior in the normal range and psychopathologies describe both ends of the same biological continuum (e. g. Montag et al., 2012). For example, the personality dimensions anxiety, neuroticism, and harm avoidance have all been related to the serotonergic system (e. g. Lesch, Bengel, Heils, & Sabol, 1996; Reuter, Kuepper, & Hennig, 2007) and drugs influencing 5-HT neurotransmission are common in the therapy of anxiety disorders (Hidalgo, Tupler, & Davidson, 2007). Personality dimensions related to negative emotionality were much more frequently investigated in the context of psychiatric disorders than those related to positive emotionality. With respect to RD there are plenty of studies reporting an association to drug addiction (e. g. Milivojevic et al., 2012; Zoccali et al., 2007) although especially novelty seeking (NS) seems to be of great importance in this domain as well (e. g. Lukasiewicz et al., 2008). RD reflects a tendency to sustain rewarding behaviors and to prefer behaviors previously associated with social reward. Whereas NS represents the drug seeking behavior in addiction, RD is more related to social reward and the maintenance of well-established behaviors. For example, opiate addicts tend to have low RD scores (Milivojevic et al., 2012). In the context of alcoholism, Cloninger (1987b) proposes a classification that distinguishes between Type I and Type II alcoholics. Type I alcoholism (the anxious type) is characterized by high HA, high RD and low NS whereas Type II alcoholics (the impulsive type) display the diametrically opposite personality configuration. Although there is plenty of evidence in the literature that supports Cloninger's biosocial personality theory and makes clearly defined assumptions on the underlying neurotransmitter systems, there are also many negative findings, especially concerning genetic association studies (e.g. Munafò et al., 2009). Moreover, the psychometric properties of the TCI have been criticized (e.g. Farmer & Goldberg, 2008). It becomes more and more apparent that there is an ultimate need for replication studies that can be used for meta-analyses (Hirschhorn et al., 2002; Munafo & Flint, 2004). This in mind the aim of the present study was to investigate the theory driven hypothesis that genetic variation on the DBH gene is associated with individual differences in RD in two independent samples of healthy participants. Cloninger postulates low noradrenaline levels in subjects scoring high on RD (Cloninger, 1987b), the functional SNP rs1611115 (C-970T) on the DBH gene is related to alterations in DBH enzymatic activity (Punchaichira et al., 2016;

Please cite this article as: Plieger, T., et al., Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples, Personality and Individual Differences (2017), http://dx.doi.org/10.1016/j.paid.2017.05.050

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Zabetian et al., 2001) and to drug addiction (Kosten et al., 2013; Xie et al., 2013). Given that rs1611115 (C-970T) and RD are both associated to addiction we hypothesized an effect of the candidate SNP on RD. Results show a significant association between rs1611115 (C-970T) and RD. The effect is stronger in the population based Sample2 in comparison to the data derived from Sample1 which is dominated by younger subjects. However, irrespective of these marked age differences between both samples the effect could be replicated. Results from both samples show that carriers of the TT genotype have significantly lower RD scores than carriers of at least one C allele (genotypes CC and CT). Zabetian et al. (2001) reported that rs1611115 could explain up to 50% of the variance in DBH activity. Two independent studies demonstrated an allelic load effect of rs1611115 on DBH activity, with highest enzymatic activity in carriers of the CC genotype, intermediate activity in heterozygous CT carriers and lowest activity in carriers homozygous for the T allele (Punchaichira et al., 2016; Zabetian et al., 2001). This finding suggests that CC carriers associated with high RD scores have high noradrenaline levels, because DBH metabolizes dopamine to noradrenaline. Therefore, the present study only supports Cloninger's general hypothesis that RD is related to noradrenaline but the directionality of the RD – noradrenaline association that high RD (C allele carriers) is related to low noradrenaline levels was not corroborated. A possible explanation is that DBH activity is likely to be dependent on the availability of its substrate, i.e. dopamine. Unfortunately, neither the existing functionality studies nor our study controlled for the availability of dopamine. The present study is a genetic association study using the classic candidate gene approach. This method has been repeatedly criticized in the past to produce highly unreliably findings (e.g. Flint & Munafò, 2013). The alternative would be the conduction of a genome wide association study (GWAS). GWAS is a completely a-theoretical and therefore explorative method, correlating millions of polymorphisms simultaneously with the phenotype under investigation. GWAS although being a great technical achievement also bears its disadvantages. The immense number of investigated polymorphisms demands extremely large samples, potential findings have again to be replicated in independent studies, and statistical findings have to be controlled for an alpha error inflation. Ironically most GWAS findings could not be replicated and sometimes the functionality of polymorphisms of replicated findings is unknown or does not make sense (for an overview see Reuter, Felten, & Montag, 2016). Therefore, the candidate gene approach and GWAS both have their legitimation. Luckily the present candidate gene approach study provides replication data and the sample size is rather large for studies in the field of genetic personality research. This will be even of advantage in the future: The larger the sample the more representative it is and this is a positive effect for future metaanalyses. Meta-analyses relying on data from numerous but underpowered samples could provide unreliable findings. In sum, this is the first study reporting an association between the functional rs1611115 (C-970T) polymorphism and RD in two independent samples. The proportion of explained variance (max. 1.7%) is not large but in the range of what can be expected when associating a single SNP to a polygenetic phenotype like RD. Therefore, further studies have to investigate more polymorphisms simultaneously, perhaps in a genome wide association study. However, we have learned from the past that especially effects of polymorphisms of which the functionality is known have been replicated in genetic association studies. A next research avenue would be to investigate the interdependency of dopamine, NA, RD and rs1611115 (C-970T).

References Barrie, E. S., Weinshenker, D., Verma, A., Pendergrass, S. A., Lange, L. A., Ritchie, M. D., ... Gerhard, G. S. (2014). Regulatory polymorphisms in human DBH affect peripheral gene expression and sympathetic activity. Circulation Research, 115(12), 1017–1025.

Bouchard, T. J., Jr., Lykken, D. T., McGue, M., Segal, N. L., & Tellegen, A. (1990, Oct 12). Sources of human psychological differences: The Minnesota Study of Twins Reared Apart. Science, 250(4978), 223–228. Carroll, K. M., Fenton, L. R., Ball, S. A., Nich, C., Frankforter, T. L., Shi, J., & Rounsaville, B. J. (2004). Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: A randomized placebo-controlled trial. Archives of General Psychiatry, 61(3), 264–272. http://dx.doi.org/10.1001/archpsyc.61.3.264. Chen, Y., Wen, G., Rao, F., Zhang, K., Wang, L., Rodriguez-Flores, J. L., ... Mahata, S. K. (2010). Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. Journal of Hypertension, 28(1), 76. Cloninger, C. R. (1986). A unified biosocial theory of personality and its role in the development of anxiety states. Psychiatric Developments, 3(2), 167–226. Cloninger, C. R. (1987a). A systematic method for clinical description and classification of personality variants: A proposal. Archives of General Psychiatry, 44(6), 573–588. Cloninger, C. R. (1987b). Neurogenetic adaptive mechanisms. Science, 236, 410–416. Cloninger, C. R., Svrakic, D. M., & Przybeck, T. R. (1993). A psychobiological model of temperament and character. Archives of General Psychiatry, 50, 975–990. Cloninger, C. R., Svrakic, D. M., & Przybeck, T. R. (2006). Can personality assessment predict future depression? A twelve-month follow-up of 631 subjects. Journal of Affective Disorders, 92(1), 35–44. Curtin, F., Walker, J. P., Peyrin, L., Soulier, V., Badan, M., & Schulz, P. (1997). Reward dependence is positively related to urinary monoamines in normal men. Biological Psychiatry, 42(4), 275–281. Farmer, R. F., & Goldberg, L. R. (2008). A psychometric evaluation of the Revised Temperament and Character Inventory (TCI-R) and the TCI-140. Psychological Assessment, 20(3), 281–291. http://dx.doi.org/10.1037/a0012934. Flint, J., & Munafò, M. R. (2013). Candidate and non-candidate genes in behavior genetics. Current Opinion in Neurobiology, 23(1), 57–61. Grabe, H. J., Spitzer, C., & Freyberger, H. J. (2004). Alexithymia and personality in relation to dimensions of psychopathology. American Journal of Psychiatry, 161(7), 1299–1301. Ham, B. J., Choi, M. J., Lee, H. J., Kang, R. H., & Lee, M. S. (2005, Jun). Reward dependence is related to norepinephrine transporter T-182C gene polymorphism in a Korean population. Psychiatric Genetics, 15(2), 145–147. Hess, C., Reif, A., Strobel, A., Boreatti-Hummer, A., Heine, M., Lesch, K. P., & Jacob, C. P. (2009). A functional dopamine-beta-hydroxylase gene promoter polymorphism is associated with impulsive personality styles, but not with affective disorders. Journal of Neural Transmission, 116(2), 121–130. http://dx.doi.org/10.1007/s00702008-0138-0. Hidalgo, R. B., Tupler, L. A., & Davidson, J. R. (2007). An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. Journal of Psychopharmacology, 21(8), 864–872. Hirschhorn, J. N., Lohmueller, K., Byrne, E., & Hirschhorn, K. (2002). A comprehensive review of genetic association studies. Genetics in Medicine, 4(2), 45–61. Kosten, T. R., Wu, G., Huang, W., Harding, M. J., Hamon, S. C., Lappalainen, J., & Nielsen, D. A. (2013). Pharmacogenetic randomized trial for cocaine abuse: Disulfiram and dopamine beta-hydroxylase. Biological Psychiatry, 73(3), 219–224. http://dx.doi.org/10. 1016/j.biopsych.2012.07.011. Lesch, K. P., Bengel, D., Heils, A., & Sabol, S. Z. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274(5292), 1527. Lukasiewicz, M., Neveu, X., Blecha, L., Falissard, B., Reynaud, M., & Gasquet, I. (2008). Pathways to substance-related disorder: A structural model approach exploring the influence of temperament, character, and childhood adversity in a national cohort of prisoners. Alcohol and Alcoholism, 43(3), 287–295. Melchers, M. C., Plieger, T., Meermann, R., & Reuter, M. (2015). Differentiating burnout from depression: Personality matters! Frontiers in Psychiatry, 6. Milivojevic, D., Milovanovic, S. D., Jovanovic, M., Svrakic, D. M., Svrakic, N. M., Svrakic, S. M., & Cloninger, C. R. (2012). Temperament and character modify risk of drug addiction and influence choice of drugs. The American Journal on Addictions, 21(5), 462–467. Montag, C., Jurkiewicz, M., & Reuter, M. (2012). The role of the catechol-O-methyltransferase (COMT) gene in personality and related psychopathological disorders. CNS & Neurological Disorders - Drug Targets, 11(3), 236–250. Montag, C., & Reuter, M. (2014). Disentangling the molecular genetic basis of personality: From monoamines to neuropeptides. Neuroscience & Biobehavioral Reviews, 43, 228–239. Mulder, R. T., Joyce, P. R., Sullivan, P. F., Bulik, C. M., & Carter, F. A. (1999). The relationship among three models of personality psychopathology: DSM-III-R personality disorder, TCI scores and DSQ defences. Psychological Medicine, 29(04), 943–951. Munafo, M. R., & Flint, J. (2004). Meta-analysis of genetic association studies. Trends in Genetics, 20(9), 439–444. Munafò, M. R., Freimer, N. B., Ng, W., Ophoff, R., Veijola, J., Miettunen, J., ... Flint, J. (2009). 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 150(2), 271–281. Plieger, T., Melchers, M., Montag, C., Meermann, R., & Reuter, M. (2015). Life stress as potential risk factor for depression and burnout. Burnout Research, 2(1), 19–24. Punchaichira, T. J., Prasad, S., Deshpande, S. N., & Thelma, B. K. (2016, Jul). Deep sequencing identifies novel regulatory variants in the distal promoter region of the dopamine-β-hydroxylase gene. Pharmacogenetics and Genomics, 26(7), 311–323. Reuter, M., Felten, A., & Montag, C. (2016). Molecular genetics. Neuroeconomics (pp. 443–461). Berlin Heidelberg: Springer. Reuter, M., Kuepper, Y., & Hennig, J. (2007). Association between a polymorphism in the promoter region of the TPH2 gene and the personality trait of harm avoidance. The International Journal of Neuropsychopharmacology, 10(03), 401–404.

Please cite this article as: Plieger, T., et al., Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples, Personality and Individual Differences (2017), http://dx.doi.org/10.1016/j.paid.2017.05.050

T. Plieger et al. / Personality and Individual Differences xxx (2017) xxx–xxx Roberts, B. W., & DelVecchio, W. F. (2000). The rank-order consistency of personality traits from childhood to old age: A quantitative review of longitudinal studies. Psychological Bulletin, 126(1), 3. Shiraishi, H., Suzuki, A., Fukasawa, T., Aoshima, T., Ujiie, Y., Ishii, G., & Otani, K. (2006, Apr). Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants. Psychiatric Genetics, 16(2), 55–58. Skinner, M. D., Lahmek, P., Pham, H., & Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: A meta-analysis. PloS One, 9(2), e87366. http://dx.doi. org/10.1371/journal.pone.0087366. Terock, J., Janowitz, D., Spitzer, C., Miertsch, M., Freyberger, H. J., & Grabe, H. J. (2015). Alexithymia and self-directedness as predictors of psychopathology and psychotherapeutic treatment outcome. Comprehensive Psychiatry, 62, 34–41. Van Os, J., Linscott, R. J., Myin-Germeys, I., Delespaul, P., & Krabbendam, L. (2009). A systematic review and meta-analysis of the psychosis continuum: Evidence for a psychosis proneness–persistence–impairment model of psychotic disorder. Psychological Medicine, 39(02), 179–195. Xie, X., Xu, L., Liu, H., Chen, W., Zhuang, D., Zhang, J., ... Zhou, W. (2013). Positive association between -1021TT genotype of dopamine beta hydroxylase gene and progressive behavior of injection heroin users. Neuroscience Letters, 541, 258–262. http://dx.doi. org/10.1016/j.neulet.2013.02.049. Yamano, E., Isowa, T., Nakano, Y., Matsuda, F., Hashimoto-Tamaoki, T., Ohira, H., & Kosugi, S. (2008, Sep–Oct). Association study between reward dependence temperament and a

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polymorphism in the phenylethanolamine N-methyltransferase gene in a Japanese female population. Comprehensive Psychiatry, 49(5), 503–507. Yang, B. Z., Balodis, I. M., Lacadie, C. M., Xu, J., & Potenza, M. N. (2016, Jun). A preliminary study of DBH (encoding dopamine beta-hydroxylase) genetic variation and neural correlates of emotional and motivational processing in individuals with and without pathological gambling. Journal of Behavioral Addictions, 5(2), 282–292. http://dx.doi. org/10.1556/2006.5.2016.026. Yu, Y. W., Yang, C. W., Wu, H. C., Tsai, S. J., Hong, C. J., Chen, M. C., & Chen, T. J. (2005). Association study of a functional MAOA-uVNTR gene polymorphism and personality traits in Chinese young females. Neuropsychobiology, 52(3), 118–121. Zabetian, C. P., Anderson, G. M., Buxbaum, S. G., Elston, R. C., Ichinose, H., Nagatsu, T., ... Cubells, J. F. (2001). A quantitative-trait analysis of human plasma-dopamine betahydroxylase activity: Evidence for a major functional polymorphism at the DBH locus. American Journal of Human Genetics, 68(2), 515–522. http://dx.doi.org/10. 1086/318198. Zoccali, R., Muscatello, M. R. A., Bruno, A., Bilardi, F., De Stefano, C., Felletti, E., ... Meduri, M. (2007). Temperament and character dimensions in opiate addicts: Comparing subjects who completed inpatient treatment in therapeutic communities vs. incompleters. The American Journal of Drug and Alcohol Abuse, 33(5), 707–715.

Please cite this article as: Plieger, T., et al., Association between a functional polymorphism on the dopamine-β-hydroxylase gene and reward dependence in two independent samples, Personality and Individual Differences (2017), http://dx.doi.org/10.1016/j.paid.2017.05.050