FOXN3 and GDNF Polymorphisms as Common Genetic Factors of Substance Use and Addictive Behaviors.

Epidemiological and phenomenological studies suggest shared underpinnings between multiple addictive behaviors. The present genetic association study was conducted as part of the Psychological and Genetic Factors of Addictions study (n = 3003) and aimed to investigate genetic overlaps between different substance use, addictive, and other compulsive behaviors. Association analyses targeted 32 single-nucleotide polymorphisms, potentially addictive substances (alcohol, tobacco, cannabis, and other drugs), and potentially addictive or compulsive behaviors (internet use, gaming, social networking site use, gambling, exercise, hair-pulling, and eating). Analyses revealed 29 nominally significant associations, from which, nine survived an FDRbl correction. Four associations were observed between FOXN3 rs759364 and potentially addictive behaviors: rs759364 showed an association with the frequency of alcohol consumption and mean scores of scales assessing internet addiction, gaming disorder, and exercise addiction. Significant associations were found between GDNF rs1549250, rs2973033, CNR1 rs806380, DRD2/ANKK1 rs1800497 variants, and the "lifetime other drugs" variable. These suggested that genetic factors may contribute similarly to specific substance use and addictive behaviors. Specifically, FOXN3 rs759364 and GDNF rs1549250 and rs2973033 may constitute genetic risk factors for multiple addictive behaviors. Due to limitations (e.g., convenience sampling, lack of structured scales for substance use), further studies are needed. Functional correlates and mechanisms underlying these relationships should also be investigated.

Association of Genetic Variation in the 3'UTR of LHX6, IMMP2L, and AADAC With Tourette Syndrome.

Background: Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression. Methods: We used an in silico approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls (n = 290), as well as TS family trios (n = 148), we performed transmission disequilibrium test (TDT) and meta-analysis. Results: We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene (p = 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene (p = 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients (p = 0.029). Conclusion: This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.

Co-occurrences of substance use and other potentially addictive behaviors: Epidemiological results from the Psychological and Genetic Factors of the Addictive Behaviors (PGA) Study.

BACKGROUND AND AIMS: Changes in the nomenclature of addictions suggest a significant shift in the conceptualization of addictions, where non-substance related behaviors can also be classified as addictions. A large amount of data provides empirical evidence that there are overlaps of different types of addictive behaviors in etiology, phenomenology, and in the underlying psychological and biological mechanisms. Our aim was to investigate the co-occurrences of a wide range of substance use and behavioral addictions. METHODS: The present epidemiological analysis was carried out as part of the Psychological and Genetic Factors of the Addictive Behaviors (PGA) Study, where data were collected from 3,003 adolescents and young adults (42.6% males; mean age 21 years). Addictions to psychoactive substances and behaviors were rigorously assessed. RESULTS: Data is provided on lifetime occurrences of the assessed substance uses, their co-occurrences, the prevalence estimates of specific behavioral addictions, and co-occurrences of different substance use and potentially addictive behaviors. Associations were found between (i) smoking and problematic Internet use, exercising, eating disorders, and gambling (ii) alcohol consumption and problematic Internet use, problematic online gaming, gambling, and eating disorders, and (iii) cannabis use and problematic online gaming and gambling. CONCLUSIONS: The results suggest a large overlap between the occurrence of these addictions and behaviors and underlies the importance of investigating the possible common psychological, genetic and neural pathways. These data further support concepts such as the Reward Deficiency Syndrome and the component model of addictions that propose a common phenomenological and etiological background of different addictive and related behaviors.

[Relationship between executive functions, body mass index and the DRD4 VNTR 7-repeat allele]. / A végrehajtó funkciók összefüggése a testtömegindexszel és a DRD4-VNTR 7-es alléllal.

Introduction and aim: Earlier results in the literature suggest that overweight subjects show weaker performance in executive function tasks as compared to normal weight people. Dopaminergic system is strongly linked to executive functions, body mass regulation and ingestion. The aim of the present study was to examine the possible relationship between DRD4 VNTR 7-repeat allele, body mass index and Stroop performance in a healthy adult population, and to draw psychogenetic conclusions. Method: 152 subjects without diabetic or psychiatric history participated in the study. Along with non-invasive DNA sampling, demographic, weight and height data were collected. The participants also solved the computerized Stroop task. 11 subjects belonged to the underweight (mean body mass index = 17.9 kg/m2), 98 subjects to the normal (mean body mass index = 21.8 kg/m2), and 43 subjects to the overweight (mean body mass index = 28.9 kg/m2) category. After grouping participants according to their body mass index and DRD4 VNTR genotype, we compared their mean performance to investigate the possible psychogenetic associations. Results: Body mass index and stimuli type showed significant interaction on error number (p = 0.045): subjects with normal body mass index made significantly less error as compared to under- and overweight subjects in incongruent trials. The 7-repeat allele carriers made tendentiously more errors than non-carriers. Normal weight people made less error - independently from their genotype -, while subjects with either low or high BMI carrying the 7-repeat allele made more errors compared to non-carriers. Conclusion: Under- and overweight subjects perform weaker where inhibition is necessary in the task. This may reflect their reactions to food-related situations. Orv Hetil. 2019; 160(39): 1554-1562.

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.

Gene-sex interaction in Hypercompetitive Attitude suggests beneficial effect of the DRD4 7-repeat allele in adaptation.

Twin studies provide evidence for the heritability of social attitudes, e.g. competitiveness, however, there are no psychogenetic association results linking competitive attitudes to genetic polymorphisms. Candidate gene studies report association with competitiveness-related phenotypes, risk taking for example was linked with the 7-repeat allele of the dopamine D4 receptor gene. This polymorphism has been studied extensively with novelty seeking and certain psychiatric disorders, as it plays a crucial role in molecular genetic mechanisms driving behavioral responses to the environment, especially modulating behavior through the reward circuitry. In the present study, we examined association of the DRD4 48-bp VNTR and competitiveness using self-report data from 399 non-related Caucasians. We found an interesting gene-sex interaction: 7-carrier males were more hypercompetitive as compared to non-carriers, while 7-carrier females were less hypercompetitive as compared to non-carriers. This finding remained significant after Bonferroni correction for multiple testing. Interestingly, among females we observed a significant positive correlation between hypercompetitiveness and mood characteristic variables, however, no such relationship could be detected in males. In 7-carrier females the association of hypercompetitiveness and anxiety or depression was more robust as compared to non-carrier females. These results highlight the importance of cultural influences in interpreting gene-sex interaction effects. Our results underlies interaction between genes and the environment; suggesting that the 7-repeat allele plays an important role in adaptivity, enabling sex-specific behavior to social expectations.

Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms.

INTRODUCTION: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. METHODS: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. RESULTS: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. CONCLUSION: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.

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.

Association between Age and the 7 Repeat Allele of the Dopamine D4 Receptor Gene.

Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population. In the present study we demonstrate the same association using continuous age groups in an 18-97 years old Caucasian sample (N = 1801, p = 0.007). We found a continuous pattern of increase from 18-75, however frequency of allele 7 carriers decreased in our oldest age groups. Possible role of gene-environment interaction effects driven by historical events are discussed. In accordance with previous findings, we observed association preferentially in females (p = 0.003). Our results underlie the importance of investigating non-disease related genetic variants as inherited components of longevity, and confirm, that the 7-repeat allele of the dopamine D4 receptor gene is a longevity enabling genetic factor, accumulating in the elderly female population.

Rapporteur summaries of plenary, symposia, and oral sessions from the XXIIIrd World Congress of Psychiatric Genetics Meeting in Toronto, Canada, 16-20 October 2015.

The XXIIIrd World Congress of Psychiatric Genetics meeting, sponsored by the International Society of Psychiatric Genetics, was held in Toronto, ON, Canada, on 16-20 October 2015. Approximately 700 participants attended to discuss the latest state-of-the-art findings in this rapidly advancing and evolving field. The following report was written by trainee travel awardees. Each was assigned one session as a rapporteur. This manuscript represents the highlights and topics that were covered in the plenary sessions, symposia, and oral sessions during the conference, and contains major notable and new findings.

Individual differences in flow proneness are linked to a dopamine D2 receptor gene variant.

Flow is a special mental state characterized by deep concentration that occurs during the performance of optimally challenging tasks. In prior studies, proneness to experience flow has been found to be moderately heritable. In the present study, we investigated whether individual differences in flow proneness are related to a polymorphism of the dopamine D2 receptor coding gene (DRD2 C957T rs6277). This polymorphism affects striatal D2 receptor availability, a factor that has been shown to be related to flow proneness. To our knowledge, this is the first study to investigate the association between this trait and a specific gene variant. In a sample of 236 healthy Hungarian adults, we found that CC homozygotes report higher flow proneness than do T allele carriers, but only during mandatory activities (i.e., studying and working), not during leisure time. We discuss implications of this result, e.g., the potential mediators of the relationship.

Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression.

BACKGROUND: Peripheral biomarkers for major psychiatric disorders have been an elusive target for the last half a century. Dermal fibroblasts are a simple, relevant, and much underutilized model for studying molecular processes of patients with affective disorders, as they share considerable similarity of signal transduction with neuronal tissue. METHODS: Cultured dermal fibroblast samples from patients with major depressive disorder (MDD) and matched control subjects (n = 16 pairs, 32 samples) were assayed for genome-wide messenger RNA (mRNA) expression using microarrays. In addition, a simultaneous quantitative polymerase chain reaction-based assessment of >1000 microRNA (miRNA) species was performed. Finally, to test the relationship between the mRNA-miRNA expression changes, the two datasets were correlated with each other. RESULTS: Our data revealed that MDD fibroblasts, when compared with matched control subjects, showed a strong mRNA gene expression pattern change in multiple molecular pathways, including cell-to-cell communication, innate/adaptive immunity, and cell proliferation. Furthermore, the same patient fibroblasts showed altered expression of a distinct panel of 38 miRNAs, which putatively targeted many of the differentially expressed mRNAs. The miRNA-mRNA expression changes appeared to be functionally connected, as the majority of the miRNA and mRNA changes were in the opposite direction. CONCLUSIONS: Our data suggest that combined miRNA-mRNA assessments are informative about the disease process and that analyses of dermal fibroblasts might lead to the discovery of promising peripheral biomarkers of MDD that could be potentially used to aid the diagnosis and allow mechanistic testing of disturbed molecular pathways.

The genetics of problem and pathological gambling: a systematic review.

BACKGROUND AND AIMS: The primary aim of the present review was to summarize the findings of genetic studies conducted on problem and pathological gambling. METHOD: Literature searches were conducted using PubMed, Medline and the HuGE Navigator databases using the keywords 'gambling' and 'genetic*'. RESULTS: The literature searches identified 21 empirical studies that had analyzed data from eight independent samples. Empirical research utilizing twin data accounted for eight of the studies, while gene association data were presented in 13 studies (including one genome wide-association study [GWAS] study). Twin studies emphasized the significant role of genetic and individual environmental factors in problem and pathological gambling. Gene association studies primarily reported the involvement of the dopaminergic and serotonergic systems. DISCUSSION: Despite the relatively low number of genetic studies, the data clearly indicated the genetic vulnerability of problem and pathological gambling. Studies to date have mainly investigated and verified the role of factors reported to be important in other types of addiction, and it is suggested that pathological gambling should be included as a subtype of 'Reward Deficiency Syndrome' (RDS). It is concluded that future research should attempt to identify possible gambling specific susceptibility factors.

Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts.

Metabolic and oxidative stresses induce physiological adaptation processes, disrupting a finely tuned, coordinated network of gene expression. To better understand the interplay between the mRNA and miRNA transcriptomes, we examined how two distinct metabolic stressors alter the expression profile of human dermal fibroblasts. Primary fibroblast cultures were obtained from skin biopsies of 17 healthy subjects. Metabolic stress was evoked by growing subcultured cells in glucose deprived, galactose enriched (GAL) or lipid reduced, cholesterol deficient (RL) media, and compared to parallel-cultured fibroblasts grown in standard (STD) medium. This was followed by mRNA expression profiling and assessment of >1000 miRNAs levels across all three conditions. The miRNA expression levels were subsequently correlated to the mRNA expression profile. Metabolic stress by RL and GAL both produced significant, strongly correlated mRNA/miRNA changes. At the single gene level four miRNAs (miR-129-3p, miR-146b-5p, miR-543 and miR-550a) showed significant and comparable expression changes in both experimental conditions. These miRNAs appeared to have a significant physiological effect on the transcriptome, as nearly 10% of the predicted targets reported changes at mRNA level. The two distinct metabolic stressors induced comparable changes in the miRNome profile, suggesting a common defensive response of the fibroblasts to altered homeostasis. The differentially expressed miR-129-3p, miR-146b-5p, miR-543 and miR-550a regulated multiple genes (e.g. NGEF, NOVA1, PDE5A) with region- and age-specific transcription in the human brain, suggesting that deregulation of these miRNAs might have significant consequences on CNS function. The overall findings suggest that analysis of stress-induced responses of peripheral fibroblasts, obtained from patients with psychiatric disorders is a promising avenue for future research endeavors.

Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence.

BACKGROUND: Heroin dependence is a debilitating psychiatric disorder with complex inheritance. Since the dopaminergic system has a key role in rewarding mechanism of the brain, which is directly or indirectly targeted by most drugs of abuse, we focus on the effects and interactions among dopaminergic gene variants. OBJECTIVE: To study the potential association between allelic variants of dopamine D2 receptor (DRD2), ANKK1 (ankyrin repeat and kinase domain containing 1), dopamine D4 receptor (DRD4), catechol-O-methyl transferase (COMT) and dopamine transporter (SLC6A3) genes and heroin dependence in Hungarian patients. METHODS: 303 heroin dependent subjects and 555 healthy controls were genotyped for 7 single nucleotide polymorphisms (SNPs) rs4680 of the COMT gene; rs1079597 and rs1800498 of the DRD2 gene; rs1800497 of the ANKK1 gene; rs1800955, rs936462 and rs747302 of the DRD4 gene. Four variable number of tandem repeats (VNTRs) were also genotyped: 120 bp duplication and 48 bp VNTR in exon 3 of DRD4 and 40 bp VNTR and intron 8 VNTR of SLC6A3. We also perform a multivariate analysis of associations using Bayesian networks in Bayesian multilevel analysis (BN-BMLA). FINDINGS AND CONCLUSIONS: In single marker analysis the TaqIA (rs1800497) and TaqIB (rs1079597) variants were associated with heroin dependence. Moreover, -521 C/T SNP (rs1800955) of the DRD4 gene showed nominal association with a possible protective effect of the C allele. After applying the Bonferroni correction TaqIB was still significant suggesting that the minor (A) allele of the TaqIB SNP is a risk component in the genetic background of heroin dependence. The findings of the additional multiple marker analysis are consistent with the results of the single marker analysis, but this method was able to reveal an indirect effect of a promoter polymorphism (rs936462) of the DRD4 gene and this effect is mediated through the -521 C/T (rs1800955) polymorphism in the promoter.

Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms.

BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BPD) have significant genetic predisposition. The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a susceptibility gene for both MDD and BPD. In the current study the genetic effects of rs2230912 (Gln460Arg) and rs1653625 (located in the 3' untranslated region of the P2RX7 gene) were explored in mood disorders. METHODS: Genotype frequencies were established in 315 patients (195 with MDD and 120 with BPD diagnosis) and in 373 controls. Depression severity was assessed by the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and by the self-report Hospital Anxiety and Depression Scale (HADS). RESULTS: In the case-control analysis we did not find any significant differences between genotype frequencies of either BPD or MDD cases and controls. However, BPD patients carrying at least one rs2230912G-allele scored higher on both MADRS and HADS-depression scale (nominal p-value was 0.028 and 0.003, respectively). The rs1653625AA genotype was also associated with higher depression scores in the BPD group (nominal p-value of MADRS: 0.019, HADS-depression: 0.017). After correction for multiple testing, the association between rs2230912 and HADS-depression score remained significant in the BPD group (p<0.006); this genetic effect explained 9% of the variance (partial η(2)=0.09). In the MDD group we did not find any significant genetic effect. LIMITATIONS: The relatively small number of BPD patients warrants for a replication study. CONCLUSIONS: Our genetic association study supports the association between P2RX7 gene and severity of depressive symptoms in BPD patients.

Asociación entre la búsqueda de novedades y el polimorfismo Val 158Met del gen de la catecol-O-metiltransferasa en pacientes dependientes de opiáceos / Association between novelty seeking of opiate-dependent patients and the catechol-O-methyltransferase Val 158Met polymorphism

Fundamento. Los genes candidatos del sistema dopaminérgico se han descrito como elementos clave en la conformación del temperamento del ser humano. La enzima catecol-O-metiltransferasa (COMT) desempeña un papel decisivo en la inactivación de la dopamina, y recientemente, en estudios efectuados en adultos sanos, al igual que en individuos dependientes de la metaanfetamina, en el cuestionario Temperament and Character Inventory el polimorfismo de un solo nucleótido Val158Met (rs4680) del gen COMT se ha asociado a la dimensión temperamental de búsqueda de novedades (BN). Método. El objetivo del presente estudio fue examinar la asociación entre las dimensiones temperamentales del cuestionario Temperament and Character Inventory y la variación Val158Met del gen COMT en una muestra húngara de 117 pacientes dependientes de la heroína y 124 individuos de control, no dependientes. Resultados. El análisis de casos-controles no demostró diferencias significativas en las distribuciones de alelo o genotipo. Sin embargo, la estrategia dimensional reveló una asociación entre el polimorfismo Val158Met del gen COMT y la dimensión temperamental de búsqueda de novedades (p=0,01): tanto en los individuos de control como en los dependientes de opiáceos con genotipos Met/Met se demostraron puntuaciones más altas para BN comparado con aquellos con el alelo Val. Las puntuaciones obtenidas para BN también fueron significativamente más altas entre dependientes de opiáceos; sin embargo, no se detectó ninguna interacción entre el estado del grupo y el genotipo del gen COMT. Conclusión. Para pacientes dependientes de la heroína e individuos de control, con independencia de la situación del grupo, se ha demostrado la asociación del polimorfismo del gen COMT y la dimensión temperamental de búsqueda de novedades (AU)

Background. Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val158Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers. Method. Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val158Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls. Results. Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val158Met and NS (P=.01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype. Conclusion. Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status (AU)

Genetic predisposition to schizophrenia: what did we learn and what does the future hold?

Schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades.

Association between Novelty Seeking of opiate-dependent patients and the catechol-O-methyltransferase Val(158)Met polymorphism.

BACKGROUND: Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val(158)Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers. METHOD: Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val(158)Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls. RESULTS: Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val(158)Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype. CONCLUSION: Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.

[The role of genetic variants of the dopaminergic system in heroin dependence]. / A dopaminerg rendszer genetikai polimorfizmusainak szerepe heroinfüggésben.

Heroin dependence is a disorder with complex inheritance. It is influenced by multiple genetic and environmental factors. This paper gives an overview on the specific risk factors in the background of heroin addiction, especially within the dopaminergic system, which is one of the most important components of the brain's reward system. In connection with the development of heroin addiction the role of the dopamine D2 and D4 receptors, the dopamine transporter and the catechol-O-methyltransferase genes is discussed. Certain polymorphisms of the most extensively studied dopamine D2 receptor gene show strong association with heroin dependence. Dopamine D4 receptor and catechol-O-methyltransferase genes are also associated with the disease, but some results are still controversial. Only few studies have been done in association with the dopamine transporter gene and substance misuse and no convincing results have been found. To unravel the contradictions and better understand the pathogenesis of the disease more research needs to be conducted.