Lack of association between the G-660C polymorphism in the dopamine transporter gene (SLC6A3) and schizophrenia in the Iranian population.

Background: Dopaminergenic system plays an essential role in the plasticity of the human brain. The dopamine transporter gene (SLC6A3) mediates active reuptake of dopamine from synapsis, terminates dopamine signals, and therefore, is implicated in a number of dopamine-related disorders like psychosis. Variations in the form of single nucleotide polymorphisms in the core promoter of the SLC6A3 gene are reported to be involved in the pathogenesis of schizophrenia. In this study, we also attempted to establish the possible role of the polymorphism G-660C in the SLC6A3 gene promoter in schizophrenia in a case-control study. Materials and Methods: The allele and genotype frequency were analyzed in an Iranian cohort of 200 unrelated patients and 200 controls using polymerase chain reaction and restriction fragment length polymorphism. Results: The genotype frequency for case and control groups was GG 100%, GC 0%, CC 0%, and GG 100%, GC 0%, CC 0%, respectively. The C allele was failed in both groups. Conclusion: Our data suggest clearly that there is no association between the -660G/C polymorphism and outcome of schizophrenia in the Iranian population.

Riesgo de déficit atencional/hiperactividad en escolares Aymara, Rapa-Nui y de Santiago de Chile: Posible contribución de polimorfismos genéticos del sistema dopaminérgico / Risk of attention deficit/hyperactivity disorder in Aymara and Rapa-Nui school children: Association with dopaminergic system polymorphisms

Background: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness or inattentiveness. Aim: To search for differences in risk for ADHD and its components among Chilean native and mixed populations and to look forpossible associations with dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms. Material and Methods: School teachers were requested to complete the Conners test, which uses DSM-IV criteria, to screen for ADHD risk among Aymara and Rapa-Nui students. Results: Rapa-Nui children from Easter Island had the highest risk of hyperactivity/impulsiveness. Aymara children from the Arica-Parinacota Region had lower scores. Although inattentiveness scores had lower differences between groups, overall ADHD score differences among studied populations were highly significant. DRD4 and DAT1 alleles had a heterogeneous distribution. Easter islanders had more divergent frequencies, mostprobably as a result of separate migration routes utilized at different timeperiods during the colonization of America and Polynesia. Conclusions: The comparison of ADHD risk parameters between Rapa-Nui and Aymara children showed marked differences. Allele distri-bution of dopamine polymorphisms in Easter Island was also significantly different from northern Chile, due probably to different colonization histories. These findings suggest that higher ADHD risk scores in Easter Island children may be linked to the presence of different DRD4 alleles.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Association between the SLC6A3 A1343G polymorphism and schizophrenia / Associação entre o polimorfismo A1343G do SLC6A3 e esquizofrenia

Epidemiological studies have demonstrated that the genetic component is an important risk factor for the development of schizophrenia. The genes that codify the different compounds of the dopaminergic system have created interest for molecular investigations in patients with schizophrenia because the antipsychotic drugs, especially those of first generation, act on this cerebral system. Thus the aim of the present study was to investigate the possible association between a new single nucleotide polymorphism (rs6347) located in exon 9 of the protein transporter (SLC6A3) and schizophrenia. The distribution of the alleles and genotypes of the studied polymorphism was investigated in a sample of 235 patients and 834 controls matched by gender and age. There were statistical differences in the allelic (χ2=5.97, 1d.f. , p=0.01, OR=1.33-1.05

Estudos epidemiológicos têm demonstrado que o componente genético é um importante fator de risco para a esquizofrenia. Os genes que codificam os diferentes componentes do sistema dopaminérgico passaram a despertar interesse para estudos moleculares em pacientes com esquizofrenia, pois os antipsicóticos, em especial os de primeira geração, exercem sua ação nesse sistema. Assim, o objetivo do presente estudo foi investigar a associação entre um novo polimorfismo de nucleotídeo único (rs6347) localizado no exon 9 do gene do transportador de dopamina (SLC6A3) e esquizofrenia. Um total de 235 pacientes e 834 controles pareados para sexo e idade foi selecionado para a investigação da distribuição dos alelos e genótipos do polimorfismo investigado entre os grupos de pacientes e controles. Houve diferenças estatisticamente significantes nas distribuições alélicas (χ2=5,97, 1d.f. , p=0,01, OR=1,33-1,05

Haplotype diversity and linkage disequilibrium at the DRD2 locus among the tribes of western and southern regions of India.

BACKGROUND: Dopamine receptor D2 (DRD2) is an important gene having functional significance in the fields of neuropsychiatry and pharmacology and also has importance in evolutionary studies. MATERIALS AND METHODS: This study was undertaken to find out the haplotype distribution and linkage disequilibrium (LD) pattern for the three TaqI sites (TaqI ‘A’, TaqI ‘B’ and TaqI ‘D’) in the DRD2 gene in 232 unrelated individuals from five ethno-linguistically distinct endogamous tribal populations; Siddis and Gonds of Uttara Kannada district, Karnataka; Varli and Kolgha of Valsad district, Gujarat; and Dangi Konkana of Dang district, Gujarat. The genotype data obtained after molecular analysis of the three DRD2 sites was subjected to statistical analysis such as calculation of allele frequencies, haplotype frequencies among others. Subsequently, a neighbor-joining tree was also constructed from the data obtained. RESULTS: The three DRD2 sites were found to be polymorphic in all the populations. All the populations showed high levels of heterozygosities. Out of the eight possible haplotypes, most populations shared seven haplotypes. Of all the populations, Siddis showed the highest frequency of the ancestral haplotype B2D2A1 (11.4%). Significant LD was found to exist for TaqI ‘A’ and TaqI ‘B’ sites in both the populations. CONCLUSION: The findings are in concurrence with those from other Indian studies, especially from Dravidian-speaking South Indian populations. Similar pattern of diversity observed for ethnically and linguistically diverse populations in the present study is indicative of complex structure of Indian populations.

Estudo de revisão dos fatores biológicos, sociais e ambientais associados com o comportamento agressivo / Study review of biological, social and environmental factors associated with aggressive behavior

OBJETIVOS: Estudar os fatores de risco relacionados ao desenvolvimento do comportamento agressivo. MÉTODO: Foi realizada uma busca em duas bases de dados eletrônicas, Medline e SciElo, por estudos retrospectivos, longitudinais e de revisão que avaliaram fatores de risco para o desenvolvimento do comportamento agressivo. RESULTADOS: Foram selecionados 11 estudos longitudinais (8 prospectivos e 3 de casos-controle) e um transversal que avaliaram os fatores de risco biológicos e socioambientais relacionados ao comportamento agressivo. Cinco estudos avaliaram a expressão gênica, cinco a exposição ao tabaco, ao álcool e a cocaína no período pré-natal, um avaliou as implicações da desnutrição precoce no desenvolvimento do comportamento agressivo e um avaliou o impacto dos maus tratos na infância. CONCLUSÃO: os principais fatores biológicos encontrados foram: genéticos (baixa expressão do gene monoaminaoxidase e do gene transportador de serotonina, variações nos genes transportador e receptor de dopamina), exposição a substâncias durante o desenvolvimento intrauterino (tabaco, álcool e cocaína) e nutricionais (desnutrição infantil). os principais fatores socioambientais encontrados foram: maus tratos na infância, pobreza, criminalidade e comportamento antissocial na infância, sendo que o maior nível de evidência esteve relacionado à negligência precoce. A interação entre fatores biológicos e ambientais pode ser catalisada por um ambiente hostil aumentando os riscos para o desenvolvimento de comportamentos agressivos.

OBJECTIVES: To study the risk factors related to the development of aggressive behavior. METHOD: A search was carried out in two electronic databases, Medline and SciElo by retrospective studies, longitudinal and review that assessed risk factors for the development of aggressive behavior. RESULTS: There were selected 11 longitudinal studies (8 prospective and 3 case-control studies) and a cross sectional study that evaluated the risk factors and socio-biological related to aggressive behavior. Five studies have evaluated gene expression, five evaluated exposure to tobacco, alcohol and cocaine in the prenatal period, one evaluated the effect of early malnutrition on the development of aggressive behavior and one assessed the impact of child maltreatment. CONCLUSION: The main biological factors were: genetic (low expression of the monoamine oxidase gene and serotonin transporter gene, variations in transporter and dopamine receptor genes), exposure to substances during intrauterine development (tobacco, alcohol and cocaine) and nutrition (malnutrition). The main environmental factors were: child abuse, poverty, crime and antisocial behavior in childhood, while the highest level of evidence was related to early neglect. The interaction between biological and environmental factors can be catalyzed by a hostile environment, increasing the risk for the development of aggressive behavior.

Combinación de genotipos DRD4 y DAT1 constituye importante factor de riesgo en miembros de familias de Santiago de Chile con déficit atencional / Combination of DRD4 and DAT1 genotypes is an important risk factor for attention déficit disorder with hyperactivity families living in Santiago, Chile

Background: Attention deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. Aún: To search forpossible associations between dopamine receptor D4 (DRD4) and dopamine transponer 1 (DATl) polymorphisms and ADHD in Chilean families. Material and methods: We extended a previous family-based discordant sib pair analysis that included 26 cases diagnosed according to DSM-IV entena and 25 controls (healthy siblings of cases), adding 14 cases and 11 controls. Results: Both loci, individually classified as homozygotes or heterozygotes for the DRD4 7-repeat and DATl 10-repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings. However, the simultaneous presence of both DRD4 7-repeat heterozygosity and DATl 10 allele homozygosity was significantly higher (22.5 percent) in cases (40), compared with (2.8 percent) unaffected siblings (36), with an odds-ratio of 10.16. Conclusions: The genotype combination DRD4/7 heterozygotes and DAT1/10 homozygotes is a high risk factors in Chilean families for ADHD. Increased density of dopamine transporters in ADHD brains, along with abundance of 7-repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene-gene interaction worthy of studies to understand the functional basis ofADHD.

Association analysis between a VNTR intron 8 polymorphism of the dopamine transporter gene (SLC6A3) and obsessive- compulsive disorder in a Brazilian sample

Family, twin and segregation analysis have provided evidences that genetic factors are implicated in the susceptibility for obsessive-compulsive disorder (OCD). Several lines of research suggest that the dopaminergic system may be involved in the pathophysiology of OCD. Thus, the aim of the present study was to investigate a possible association between a polymorphism located in intron 8 of the dopamine transporter gene (SLC6A3) and OCD in a Brazilian sample composed by 208 patients and 865 healthy controls. No statistically differences were observed in allelic and genotype distributions between cases and controls. No association was also observed when the sample was divided according to specific phenotypic features such as gender, presence of tic disorders co-morbidity and age at onset of obsessive-compulsive symptoms (OCS). Our results suggest that the intron 8 VNTR of the SLC6A3 investigated in this study is not related to the susceptibility for OCD in our Brazilian sample.

Estudos de família, gêmeos e de segregação têm demonstrado que fatores genéticos estão envolvidos na susceptibilidade para o desenvolvimento do transtorno obsessivo-compulsivo (TOC). Várias linhas de pesquisa sugerem que o sistema dopaminérgico possa estar envolvido na fisiopatologia do TOC. Assim, o objetivo do presente estudo foi investigar uma possível associação entre o polimorfismo localizado no intron 8 do gene do transportador da dopamina (SLC6A3) e o TOC em uma amostra brasileira composta por 208 pacientes e 865 controles sadios. Nenhuma diferença estatisticamente significante foi observada nas distribuições alélicas e genotípicas entre os grupos de pacientes e controles. Nenhuma associação também foi observada quando as amostras foram divididas de acordo com características fenotípicas específicas, tais como gênero, presença de co-morbidade com tiques e idade de início dos sintomas obsessivo-compulsivo (SOC). Nossos resultados sugerem que o VNTR do intron 8 investigado neste estudo não está relacionado com o TOC na nossa amostra brasileira.

Lack of Association between Polymorphisms of the Dopamine Receptor D4 and Dopamine Transporter Genes and Personality Traits in a Korean Population

Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.