Genetics of gambling disorder and related phenotypes: The potential uses of polygenic and multifactorial risk models to enable early detection and improve clinical outcomes.

Gambling Disorder (GD) is an impactful behavioural addiction for which there appear to be underpinning genetic contributors. Twin studies show significant GD heritability results and intergenerational transmission show high rates of transmission. Recent developments in polygenic and multifactorial risk prediction modelling provide promising opportunities to enable early identification and intervention for at risk individuals. People with GD often have significant delays in diagnosis and subsequent help-seeking that can compromise their recovery. In this paper we advocate for more research into the utility of polygenic and multifactorial risk modelling in GD research and treatment programs and rigorous evaluation of its costs and benefits.

Underlying Mechanisms Involved in Gambling Disorder Severity: A Pathway Analysis Considering Genetic, Psychosocial, and Clinical Variables.

Gambling Disorder (GD) has a complex etiology that involves biological and environmental aspects. From a genetic perspective, neurotrophic factors (NTFs) polymorphisms have been associated with the risk of developing GD. The aim of this study was to assess the underlying mechanisms implicated in GD severity by considering the direct and mediational relationship between different variables including genetic, psychological, socio-demographic, and clinical factors. To do so, we used genetic variants that were significantly associated with an increased risk for GD and evaluated its relationship with GD severity through pathway analysis. We found that the interaction between these genetic variants and other different biopsychological features predicted a higher severity of GD. On the one hand, the presence of haplotype block 2, interrelated with haplotype block 3, was linked to a more dysfunctional personality profile and a worse psychopathological state, which, in turn, had a direct link with GD severity. On the other hand, having rs3763614 predicted higher general psychopathology and therefore, higher GD severity. The current study described the presence of complex interactions between biopsychosocial variables previously associated with the etiopathogenesis and severity of GD, while also supporting the involvement of genetic variants from the NTF family.

Differential transcriptome profile underlying risky choice in a rat gambling task.

Background and aims: Proper measurement of expected risk is important for making rational decisions, and maladaptive decision making may underlie various psychiatric disorders. However, differentially expressed genetic profiling involved in this process is still largely unknown. A rodent version of the gambling task (rGT) has been developed to measure decision-making by adopting the same principle of Iowa Gambling Task in humans. In the present study, we examined using next-generation sequencing (NGS) technique whether there are differences in gene expression profiles in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) when rats make different choices toward risk in rGT. Methods: Rats were trained in a touch screen chamber to learn the relationships between 4 different light signals on the window of the screen and accompanied reward outcomes or punishments set up with different magnitudes and probabilities. Once they showed a stabilized pattern of preference upon free choice, rats were classified into risk-averse or risk-seeking groups. After performing the rGT, rats were decapitated, the mPFC and the NAc was dissected out, and NGS was performed with the total RNA extracted. Results: We found that 477 and 36 genes were differentially expressed (approximately 75 and 83% out of them were downregulated) in the mPFC and the NAc, respectively, in risk-seeking compared to risk-averse rats. Among those, we suggested a few top ranked genes that may contribute to promoting risky choices. Discussion and conclusions: Our findings provide insights into transcriptional components underlying risky choices in rats.

The role of neurotrophin genes involved in the vulnerability to gambling disorder.

Evidence about the involvement of genetic factors in the development of gambling disorder (GD) has been assessed. Among studies assessing heritability and biological vulnerability for GD, neurotrophin (NTF) genes have emerged as promising targets, since a growing literature showed a possible link between NTF and addiction-related disorders. Thus, we aimed to explore the role of NTF genes and GD with the hypothesis that some NTF gene polymorphisms could constitute biological risk factors. The sample included 166 patients with GD and 191 healthy controls. 36 single nucleotide polymorphisms (SNPs) from NTFs (NGF, NGFR, NTRK1, BDNF, NTRK2, NTF3, NTRK3, NTF4, CNTF and CNTFR) were selected and genotyped. Linkage disequilibrium (LD) and haplotype constructions were analyzed, in relationship with the presence of GD. Finally, regulatory elements overlapping the identified SNPs variants associated with GD were searched. The between groups comparisons of allele frequencies indicated that 6 SNPs were potentially associated with GD. Single and multiple-marker analyses showed a strong association between both NTF3 and NTRK2 genes, and GD. The present study supports the involvement of the NTF family in the aetiopathogenesis of GD. An altered cross-regulation of different NTF members signalling pathways might be considered as a biological vulnerability factor for GD.

The schizophrenia risk gene Map2k7 regulates responding in a novel contingency-shifting rodent touchscreen gambling task.

In schizophrenia, subjects show reduced ability to evaluate and update risk/reward contingencies, showing correspondingly suboptimal performance in the Iowa gambling task. JNK signalling gene variants are associated with schizophrenia risk, and JNK modulates aspects of cognition. We therefore studied the performance of mice hemizygous for genetic deletion of the JNK activator MKK7 (Map2k7+/- mice) in a touchscreen version of the Iowa gambling task, additionally incorporating a novel contingency-switching stage. Map2k7+/- mice performed slightly better than wild-type (WT) littermates in acquisition and performance of the task. Although Map2k7+/- mice adapted well to subtle changes in risk/reward contingencies, they were profoundly impaired when the positions of 'best' and 'worst' choice selections were switched, and still avoided the previous 'worst' choice location weeks after the switch. This demonstrates a precise role for MKK7-JNK signalling in flexibility of risk/reward assessment and suggests that genetic variants affecting this molecular pathway may underlie impairment in this cognitive domain in schizophrenia. Importantly, this new contingency shift adaptation of the rodent touchscreen gambling task has translational utility for characterising these cognitive subprocesses in models of neuropsychiatric disorders.

Childhood maltreatment and disordered gambling in adulthood: disentangling causal and familial influences.

BACKGROUND: Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG. METHODS: Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates. RESULTS: Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality. CONCLUSIONS: These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.

Predicting disordered gambling across adolescence and young adulthood from polygenic contributions to Big 5 personality traits in a UK birth cohort.

BACKGROUND AND AIMS: Previous research has demonstrated phenotypical associations between disordered gambling (DG) and Big 5 personality traits, and a twin study suggested that shared genetic influences accounted for a substantial portion of this relation. The present study examined associations between DG and polygenic scores (PSs) for Big 5 traits to measure the shared genetic underpinnings of Big 5 personality traits and DG. DESIGN: Zero-inflated negative binomial regression models estimated associations between Big 5 PSs and past-year and life-time assessments of DG in a longitudinally assessed population-based birth cohort. SETTING: United Kingdom. PARTICIPANTS: A total of 4729 unrelated children of European ancestry from the Avon Longitudinal Study of Parents and Children (ALSPAC) with both phenotypical and genetic data. MEASUREMENTS: Phenotypical outcomes included past-year assessment of DG using the problem gambling severity index (PGSI) and life-time assessment of DSM-IV pathological gambling symptoms (DPG) across the ages of 17, 20 and 24 years. Polygenic scores were derived for the Big 5 personality traits of agreeableness, extraversion, conscientiousness, openness and neuroticism using summary statistics from genome-wide association studies (GWAS). FINDINGS: PSs for agreeableness [ß= - 0.25, standard error (SE) = 0.054, P = 3.031e-6, ΔR2 = 0.008] and neuroticism (ß=0.14, SE = 0.046, P = 0.0017, ΔR2 = 0.002) significantly predicted PGSI scores over and above included covariates (i.e. sex and first five ancestral principal components). PSs for agreeableness (ß= - 0.20, SE = 0.056, P = 0.00036, ΔR2 = 0.003) and neuroticism, when interactions with age were taken into account (ß = 0.29, SE = 0.090, P = 0.002, ΔR2 = 0.004), also predicted DPG scores. CONCLUSIONS: Polygenic contributions to low agreeableness and high neuroticism appear to predict two measures of disordered gambling (problem gambling severity index and life-time assessment of DSM-IV pathological gambling symptoms). Polygenic scores for neuroticism interact with age to suggest that the positive association becomes stronger from adolescence through young adulthood.

The structure and subtypes of gambling activities: Genetic, psychiatric and behavioral etiologies of gambling frequency.

The multitude of gambling activities has given rise to heterogeneous ways of analyzing these behaviors and may partially underlie the lack of replication in gambling research. The current study used complementary analyses to investigate the structure, typology and etiology of gambling behaviors in a discovery sample of 2,116 twins (54.86% female; Mage = 24.90) and a replication sample of 619 siblings (30.37% female; Mage = 28.00). Our approach was twofold. First, we used confirmatory factor analyses to investigate the structure across the frequency of eight gambling activities. Second, we used factor mixture models to identify gambling frequency subtypes. We assessed associations with gambling frequency as well as conducted genetically informed analyses to estimate the role of genetic and environmental influences. Across samples, a two-factor model fit the data best, with a Common Gambling factor influencing all activities and a separate factor for Skill Gambling. Our study identified four gambling frequency subtypes, which resembled the typology from the Pathways Model. We found distinct demographic, psychiatric, behavioral and genetic risk profiles for the different gambling factors and subtypes with robust associations observed for male sex, risk-taking, sensation seeking, alcohol dependence and problem gambling. Controlling for shared genetic and environmental influences (via co-twin control modeling), we found that sensation seeking directly increased Common Gambling frequency. In sum, we illustrated the utility of multi-dimensional statistical techniques for disentangling the structure and typology from complex multivariate gambling data.

Contributions of Nicholas Martin to Gambling Disorder Research.

Professor Nicholas G. Martin, from QIMR Berghofer Medical Research Institute in Brisbane, Australia, is a world leader in the effort to understand the genetic architecture underlying disordered gambling. This article pays tribute to Nick and his almost two decades of gambling research, highlighting his many strengths, ranging from the use of ingenious recruitment approaches, twin study methods, genomewide association studies, to facilitating international collaborations.

A neuroeconomic investigation of 5-HTT/5-HT1A gene variation, social anxiety, and risk-taking behavior.

Background and objectives: Although approaches combining behavioral genetics and neuroeconomics have advanced models of addiction, no study has synthesized these methods to elucidate mechanisms of competing risk-approachand risk-avoidance in social anxiety (SA). Grounded in dual-mode models of serotonergic systems and self-regulation, this study investigated associations between SA, serotonin transporter 5-HTT (LPR; rs25531) and receptor 5-HT1A genes, and risk-taking on behavioral and self-report measures.Design and methods: Young adults (N = 309) completed a neuroeconomic task measuring gambling attractiveness (δ), reward probability discrimination (γ), and risk attitudes (α). Risk genotypes included 5-HTT (LPR; rs25531) low-expression variants (SS/SLG/LGLG), and 5-HT1A (rs6295) GG.Results: Path analysis revealed that SA related to increased gambling attractiveness, but only for 5-HT1A risk groups. Although the 5-HTT (LPR; rs25531) risk genotypes and self-reported SA predicted lower social risk-taking, high-SA individuals who exhibited more accurate reward probability discrimination (γ) reported taking increased social risks.Conclusion: In line with dual-mode models, results suggest that SA predicts behavioral risk-approach at the basic decision-making level, along with self-reported social risk-avoidance, modulated by serotonergic genotypes. High-SA individuals with more accurate assessments of reward probabilities may engage in greater social risk-taking, perhaps reflecting an adaptive tendency to approach feared situations.

Striatal dynamics as determinants of reduced gambling vulnerability in the NHE rat model of ADHD.

The Naples High-Excitability (NHE) is a validated rat strain to model for a mesocortical variant of Attention Deficit Hyperactivity Disorder (ADHD). NHE rats' brains have a tuned-down cortical and a potentiated limbic loop (Zoratto et al., 2017). ADHD and comorbid pathological gambling (PG) involve similar deficits of prefrontal-striatal dialogue. This work aimed to understand if NHE rats (compared to normal random-bred rats, NRB) can be a useful model for gambling vulnerability in ADHD. Experiment 1 evaluated gambling proneness in NHE rats, namely attraction/avoidance in nose-poking for a "Large & Luck-Linked" (LLL) reward (versus a "Small & Sure" one, SS), when the probability of LLL delivery was progressively reduced. Experiment 2 assessed (by phMRI) differential responsivity of ventral (vStr) versus dorsal (dStr) striatum following a methylphenidate (MPH, 4 mg/kg I.P.) challenge. In NHE rats, reduced attraction by secondary cues (associated with uncertain, rarefying LLL delivery) comes along with little or no activation of dStr and enhanced activation of vStr by MPH. Together, such evidences from NHE rats indicate distinctive roles of ventral (enhanced value given to actual primary reward) and dorsal (lower encoding of repeated stimulus-reward associations into a habit) striatum. In conclusion, the dynamics of reward systems could link an attention deficit with a decreased vulnerability to pathological gambling.

Gambling and substance use: Comorbidity and treatment implications.

Gambling disorder is a common condition that was previously listed as an impulse control disorder, but is now considered a substance-related and addictive disorder. Gambling disorder has been associated with various untoward long-term outcomes including impaired quality of life, relationship break-ups, debt and mortgage foreclosure, and elevated risk of suicidality. This paper provides a concise primer on gambling disorder, with a special focus on its parallels with substance use disorders. We consider clinical presentations, comorbid expression, heritability, and treatment approaches (psychological and pharmacological). Lastly, we highlight new treatment directions suggested by the literature.

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

Associations among the opioid receptor gene (OPRM1) A118G polymorphism, psychiatric symptoms, and quantitative EEG in Korean males with gambling disorder: A pilot study.

BACKGROUND AND AIMS: A single nucleotide polymorphism of A118G (SNP; rs1799971) in the opioid receptor µ-1 (OPRM1) gene is a missense variant that influences the affinity of µ-opioid receptors. This study aimed to investigate the associations among the A118G polymorphism in the OPRM1 gene, psychiatric symptoms, and quantitative electroencephalography (qEEG) findings in patients with gambling disorder. METHODS: Fifty-five male patients with gambling disorder aged between 18 and 65 years old participated in the study. The A118G polymorphism was genotyped into the AA, GA, and GG groups by the polymerase chain reaction/restriction fragment length polymorphism method. Resting-state qEEG was recorded with the eyes closed, and the absolute power of the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequency bands was analyzed. Psychiatric symptoms, including depression, anxiety, impulsivity and severity of gambling, were assessed by a self-rating scale. RESULTS: There were no significant differences in psychiatric symptoms among the three genotype groups (AA, GA, and GG). However, the frequency band power of qEEG showed significant differences among the three genotype groups. The absolute power of the beta and theta bands in the frontal lobe was higher in G allele carriers. DISCUSSION AND CONCLUSION: Based on the findings of this study, the polymorphism in the OPRM1 gene might affect the neurophysiological process in patients with gambling disorder.

Association of GDNF and CNTNAP2 gene variants with gambling.

BACKGROUND AND AIMS: Some form of gambling can be observed in nearly every society, as the gratification felt upon winning in uncertain conditions is universal. A culturally distinct form of gambling, associated with a traditional sporting event of archery known as "teer," is innate to the province of Meghalaya, India. The objective of this study was to find genetic variants underlying this unique form of behavioral addiction. To better understand game-based gambling, we studied genetic variants related to dopaminergic pathways and other genes previously linked to various psychological disorders. METHODS: This study was carried out on a sample of 196 Indo-Aryan adults from Shillong, Meghalaya. Genotyping of glial cell line-derived neurotrophic factor (GDNF) polymorphisms was carried out using real-time PCR. We further investigated 32 single nucleotide polymorphisms located in the 3' UTR of additional genes of interest using an OpenArray® real-time PCR platform. RESULTS: Case-control analysis revealed a significant association between GDNF variant rs2973033 (p = .00864, χ2 = 13.132, df = 2) and contactin-associated protein-like 2 (CNTNAP2) variant rs2530311 (p = .0448, χ2 = 13.132, df = 2) with gambling. DISCUSSION AND CONCLUSIONS: Association of the GDNF gene with gambling could be attributed to its involvement in the development and survival of dopaminergic neurons. Our result is in good agreement with previous data indicating the role of GDNF in certain substance addictions. Several rare variants in the CNTNAP2 gene were also implicated in alcohol addiction in a previous study. This pilot study provides further support for the role of GDNF and CNTNAP2 in addiction behaviors.

Longitudinal interplay between gambling participation and substance use during late adolescence: A genetically-informed study.

Substance use and gambling participation during adolescence are correlated, both concurrently and over time. It is unclear, however, whether this association can be explained by common underlying genetic vulnerabilities or environmental factors. The present study explored the concurrent and longitudinal associations between substance use and gambling participation and their genetic and environmental underpinnings by late adolescence. Participants were 373 pairs of monozygotic and dizygotic twins. Self-reports of substance use and gambling participation were collected at Ages 17 and 19 years. Results showed concurrent associations between substance use and gambling participation as well as a small, but significant unidirectional longitudinal association over time from substance use to gambling participation. Common genetic factors largely accounted for the concurrent associations at Ages 17 and 19, as well as for the unidirectional longitudinal association between substance use and gambling participation. Substance use and gambling participation share a common genetic component that account for most of their concurrent and longitudinal links during late adolescence. However, these behaviors are also influenced by specific environmental factors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Oxytocin moderates risky decision-making during the Iowa Gambling Task: A new insight based on the role of oxytocin receptor gene polymorphisms and interventional cognitive study.

The oxytocinergic system influences attentional bias towards emotional cues and feedback-based learning. Considering a tag single-nucleotide polymorphism (SNP) found through analysis of an intronic haplotype in the oxytocin receptor (OXTR) gene, we investigated the effect of oxytocin on risky decision-making via the Iowa Gambling Task (IGT). Young healthy males received intranasal oxytocin or placebo, and the IGT was performed where raw scores, net scores and total time were recorded, and ratio of advantageous to disadvantageous choices was calculated. Using PCR-pyrosequencing, a 761 bp target sequence in the OXTR gene was amplified and sequenced after the extraction of whole blood DNA. Employing Haploview, haplotypes and linkage disequilibrium (LD) pattern among all 14 SNPs in the intronic region were determined based on D' and LOD values, and rs2254295 with the highest LD was indicated as the tag SNP. GTT was shown to have the highest frequency among the found haplotypes. Oxytocin group and participants with the TT genotype demonstrated a significantly increased raw score, net score and advantageous choices, whereas the total time was not influenced remarkably. This means that oxytocin significantly reduced the risk taking in decision-making, and participants with the TT genotype had less premature or risky decisions than those with the CT and CC genotypes. rs2254295 may modulate the function or expression of the OXTR gene, implying that T allele may increase the expression of the OXTR gene compared to C allele. We suggest that oxytocin may remarkably moderate the risk attitude and its consequences during uncertain decision-making.

The psychological and genetic factors of the addictive behaviors (PGA) study.

OBJECTIVES: Most of the addiction studies focus on very specific aspects of addictions, often with contradictory results, and integrated studies are quite rare. Experimental studies comparing underlying mechanisms of addictions and analyzing data from an integrative psychological and genetic perspective are almost nonexistent. The aim of the present paper is to describe the research protocol of the Psychological and Genetic Factors of Addictive Behaviors (PGA) study, which applies an integrative approach to understanding the acquisition, development, and maintenance of addictive behaviors. METHODS: A wide-spectrum national study was carried out. Data were collected from 3,003 adolescents. Addictions to both psychoactive substances and behaviors were thoroughly assessed via psychometrically robust scales, which also included assessment related to a wide range of related psychological dimensions. Additionally, a DNA sample was also collected from participants. RESULTS: The paper presents the detailed methodology of the PGA study. Data collection procedures, instrumentation, and the analytical approach used to attain the research objectives are described. CONCLUSIONS: Future plans, along with potential contributions of the PGA study, are also discussed. It is envisaged that the study will provide a unique opportunity to test possible mechanisms and causal pathways mediating the associations of genetic factors, psychological characteristics, and addictions.

Genetic and environmental influences on gambling disorder liability: a replication and combined analysis of two twin studies.

BACKGROUND: Gambling disorder (GD), recognized in Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) as a behavioral addiction, is associated with a range of adverse outcomes. However, there has been little research on the genetic and environmental influences on the development of this disorder. This study reports results from the largest twin study of GD conducted to date. METHODS: Replication and combined analyses were based on samples of 3292 (mean age 31.8, born 1972-79) and 4764 (mean age 37.7, born 1964-71) male, female, and unlike-sex twin pairs from the Australian Twin Registry. Univariate biometric twin models estimated the proportion of variation in the latent GD liability that could be attributed to genetic, shared environmental, and unique environmental factors, and whether these differed quantitatively or qualitatively for men and women. RESULTS: In the replication study, when using a lower GD threshold, there was evidence for significant genetic (60%; 95% confidence interval (CI) 45-76%) and unique environmental (40%; 95% CI 24-56%), but not shared environmental contributions (0%; 95% CI 0-0%) to GD liability; this did not significantly differ from the original study. In the combined analysis, higher GD thresholds (such as one consistent with DSM-5 GD) and a multiple threshold definitions of GD yielded similar results. There was no evidence for quantitative or qualitative sex differences in the liability for GD. CONCLUSIONS: Twin studies of GD are few in number but they tell a remarkably similar story: substantial genetic and unique environmental influences, with no evidence for shared environmental contributions or sex differences in GD liability.

Risk-seeking for losses is associated with 5-HTTLPR, but not with transient changes in 5-HT levels.

RATIONALE: Serotonin (5-HT) plays a key role in different aspects of value-based decision-making. A recent framework proposed that tonic 5-HT (together with dopamine, DA) codes future average reward expectations, providing a baseline against which possible choice outcomes are compared to guide decision-making. OBJECTIVES: To test whether high 5-HT levels decrease loss aversion, risk-seeking for gains, and risk-seeking for losses. METHODS: In a first session, 611 participants were genotyped for 5-HTTLPR and performed a mixed gambles (MGA) task and two probability discounting tasks for gains and losses, respectively (PDG/PDL). Afterwards, a subsample of 105 participants (44 with S/S, 6 with S/L, 55 with L/L genotype) completed the pharmacological study using a crossover design with tryptophan depletion (ATD), loading (ATL), and balanced (BAL) conditions. The same decision constructs were assessed. RESULTS: We found increased risk-seeking for losses in S/S compared to L/L individuals at the first visit (p = 0.002). Neither tryptophan depletion nor loading affected decision-making, nor did we observe an interaction between intervention and 5-HTTLPR genotype. CONCLUSION: Our data do not support the idea that transient changes of tonic 5-HT affect value-based decision-making. We provide evidence for an association of 5-HTTLPR with risk-seeking for losses, independent of acute 5-HT levels. This indicates that the association of 5-HTTLPR and risk-seeking for losses is mediated via other mechanisms, possibly by differences in the structural development of neural circuits of the 5-HT system during early life phases.