Relationship between aggressive behavior in patients with bipolar disorder and DRD4 gene polymorphism and personality characteristics / 上海交通大学学报（医学版）

Objective: To explore the relationship between aggressive behavior, dopamine receptor D4 (DRD4) exon III 48 bp variable number tandem repeat (VNTR) and personality characteristics in patients with bipolar disorder. Methods: From January 2015 to December 2018, 173 patients with bipolar disorder were selected from Shanghai Changning Mental Health Center, Shanghai Jing'an Mental Health Center, Shanghai Xuhui Mental Health Center, and Shanghai Jiading Central Hospital. According to the score of Modified Overt Aggression scale (MOAS), 173 patients were divided into aggressive behavior group (research group) and non-aggressive behavior group (control group). General survey and the temperament and personality questionnaire (Temperature and Character Inventory, TCI) were carried out, respectively. The polymorphism of DRD4 gene were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. Genetic equilibrium test of genotype Hardy-Weinberg and the difference of genotype frequency between the two groups were analyzed by using SHEsis software. The relationship between aggression behavior and DRD4 gene polymorphism and personality traits in bipolar disorder patients was analyzed by χ2 test and t test. Results: There was no significant difference in the general data between research group and control group (P>0.05). Six alleles and nine genotypes of DRD4 exon III 48 bp VNTR were detected. The most common alleles in the two groups were four repeat alleles. There were statistical differences in the frequency distribution of genotypes and alleles of DRD4 exon III 48 bp VNTR between the two groups (P=0.040, P=0.018). The scores of novelty seeking and harm avoidance in the research group were higher than those in the control group (P=0.026, P=0.000), while the scores of cooperativeness and self-directedness were lower than those in the control group (both P=0.000). Patients with long repeat alleles had significantly higher scores in novelty seeking and harm avoidance, and lower scores in cooperativeness, compared with patients with short repeat alleles (P=0.000, P=0.006, P=0.038). Conclusion: Aggressive behavior in patients with bipolar disorder may be associated with DRD4 exon III 48 bp VNTR. In bipolar disorder, patients with aggressive behavior have unique personality characteristics in impulsiving, novelty-seeking, exploring, being afraid of uncertainty, revengeful, behaving himself and so on. Patients with long repeat alleles have more significant personality abnormalities.

Association of methylation status of CpG islands in DAT1 and DRD4 genes with attention deficit hyperactivity disorder / 中华行为医学与脑科学杂志

Objective To explore the difference of methylation status of CpG island in promoter re?gion of DAT1 and DRD4 genes between children with attention deficit hyperactivity disorder ( ADHD) and normal controls,and further understand the pathogenesis of ADHD from a epigenetics point of view. Methods 111 ADHD patients and 118 normal controls were enrolled in the present study. The demographic data and peripheral venous blood were collected from both groups. Bisulfite genomic sequencing ( BGS) was used to confirm the methylation status of every CpG site in promoter region of DAT1 and DRD4 genes. Results No significant differences were found between ADHD patients and normal controls on percentage of methylated CpG sites in total CpG islands for both DAT1 and DRD4 (P>0.05) . However,the percentage of methylation in No. 17 CpG site for DAT1 and No. 8 CpG site for DRD4 was higher in ADHD patients ( 23. 42% and 64.86% respectively)compared with that in normal controls(11.86% and 47.46% respectively)(P<0.05).In all samples,the percentage of methylated CpG site in total CpG island for DAT1 was higher in males com?pared with that in females(P<0.05),whereas that for DRD4 was higher in females compared with that in males (P<0.05);the same gender difference on methylation level for DAT1 was also found in ADHD patients and for DRD4 in normal controls(P<0.05) . In all samples and in ADHD patients,percentage of methylated CpG site in total CpG island for DAT1 was higher in individuals over 7 years old compared with that in indi?viduals younger than or equal to 7 years old(P<0.05). Conclusions Methylation status of CpG island in DAT1 and DRD4 genes promoter region might correlate with ADHD susceptibility.Methylation status of CpG island in DAT1 and DRD4 genes show differences in different age span and sex.

Relationship of the functional polymorphism of dopamine D4 receptor gene with behavioral problems in school-age twins / 中华行为医学与脑科学杂志

Objective To investigate the correlation and characteristic of the functional polymorphism of the dopamine D4 receptor gene on the behavioral problems in school-age twins.Method The behavioral problems were assessed among a total of 147 twin pairs aged 6-12 years with the Achenbach Child Behavior Checklist (CBCL).The DRD4 gene polymorphism was applied for different types with polymerase chain reaction.The generalized estimating equations model was used to analyze the effect of DRD4 gene polymorphism and the interaction of DRD4 gene polymorphism with children age,gender,monozygotic/dizygotic on twins' behavioral problems.Results (1) School-age children's anxiety/depression,withdrawn,thought problems,attention problems,social problems,delinquent problems,aggressive behavior and total variance mainly were correlated with DRD4 gene polymorphism (P＜0.05),and physical discomfort might be related with DRD4 gene polymorphism (P=0.067).Except social problems,the detection rate of behavioral problems of the twins with 4/6 genotype (Gene type carrying 5 or more repeated sequences) of DRD4 gene (6.25％-21.25％) was higher than those with other genotypes (0-14.74％).(2) Withdrawal was related to children age (x2=4.348,P＜0.05),and twins aged 6-10 might lead to withdrawal.(3) The interaction of DRD4 gene polymorphism and children age had a significant effect on withdrawal (x2=4.348,P＜0.05) and physical discomfort(x2 =5.189,P＜0.05),and the elder age (11-12 years) children had a certainly protective effect on the withdrawal and physical discomfort with 4/6 genotype in twins.The detection rates were 3.54％ and 2.65％ in the younger-age (6-10 years) twins,while all 0 in the elder-age (11-12 years) for the withdrawal and the physical discomfort respectively.Conclusions The DRD4 gene polymorphism may be correlated with behavioral problems in school-age twins.The interaction of DRD4 polymorphism and children age had a significantly effect on withdrawal and physical discomfort.

Association between methylation status of CpG island in DAT1 and DRD4 genes and clinical symptoms of ADHD / 中国神经精神疾病杂志

Objective To investigate the correlation of methylation status in DA T1 and DRD4 genes and severity of clinical manifestations in ADHD patients.Methods One hundrd eleven DSM-Ⅳ defined ADHD patients were enrolled in this study and the demographic data were collected.Clinical symptoms were also assessed by Attention Deficit Hyperactivity Disorder Rating Scale-Ⅳ Home Version (ADHD-RS-Ⅳ) and self-developed Oppositional Defiant Disorder (ODD) rating scale.Bisulfite genomic sequencing (BGS) was used to detect the methylation status of every CpG site in DA T1 and DRD4 promoter CpG island in peripheral venous blood.Results The DNA methylation level in total CpG island for DA T1 was higher in individuals without depression,anxiety or ADHD family history compared to individuals with above family histories (P＜0.05).The differences on methylation levels for DA T1 and DRD4 were not significant between high and low ADHD-RS-Ⅳ total score (≤30 vs.＞30),ADHD-RS-Ⅳ inattention score (≤ 17 vs.＞17),and ADHD-RS-Ⅳ hyperactivity/impulsivity score (≤13 vs.＞13) subgroups (all P＜0.05).The methylation levels in total CpG island in DA T1 was higher in individuals whose ODD score were ＜9 compared to those whose ODD score were ≥9 (P＜0.05).Conclusions Methylation status of CpG island in DAT1 may influence the severity of oppositional defiant symptom in ADHD patients,which is correlated with depression,anxiety and ADHD family histories.

Identification and Characterization of Dopamine D4 Receptor (DRD4) Gene Sequence within and Among Non Mammalian Species.

A number of polymorphic tandem repeats in human dopamine D4 receptor (DRD4) have been identified in the exons, including a 12-bp repeat in the first exon and a 48-bp repeat in exon III located in the third cytoplasmic loop. However, to determine whether the tandem repeats is specific to humans or not, we have identified and characterized dopamine receptor D4 (DRD4) Exon III tandem repeats in public available nucleotide sequences from 13 different non mammalian species. We found that the tandem repeat was composed of 21-bp modules in sequences from the Mycobacterium smegmatis str. MC2 155, Salinibacter ruber DSM 13855, Danio rerio, Parus major, Corvus macrorhynchos, and Coturnix japonica. A tandem repeat consisting of 30-bp modules was identified in sequence from Melopsittacus undulates while in the Phalacrocorax capillatus and Numida meleagris we identified tandem repeats composed of 3-bp modules. Tandem repeats could not be identified in sequences from Carassius auratus, Phasianus colchicus and Gallus gallus. To understand the evolutionary history of the Exon I region of DRD4—which in humans contains a polymorphic 12bp tandem duplication, a polymorphic 13bp deletion, and other rare variants—we examined the homologous exon in these different species. There was a low degree of similarity between the sequences of bacterial species and those from members of the piscean and avian and with human sequence. We identified transmembrane domain of DRD4 gene and signature of G-protein coupled receptors in the amino acid sequences. The number of transmembrane segments varied pronouncedly between species from 0 to 7 and signature of G-protein coupled receptors was found only in piscean species and was also identified in one avian species (parus major). These findings suggest that an association between Drd4 gene polymorphisms and animal personality variation predates the divergence of the non mammalian and mammalian lineages. Furthermore, the analysis of Drd4 polymorphisms within and among populations may provide information for elucidating the phylogenetic relationship and such data may also provide a clue toward understanding the relation between the genetic variation and behavioral variation in animals.

Estudio de la variabilidad genética del DRD4 y del DAT1 en individuos habitantes de la Ciudad de México / Genetic variability study of DRD4 and DAT1 in the urban population of Mexico City

Family, twin and adoption studies suggest that genetics plays an important role in the etiology of many psychiatric disorders. It has been proposed that the dopaminergic brain system could be affected in schizophrenia, substance abuse and attention deficit hyperactivity disorder. The most studied genes are two VNTR polymorphic systems; one located in the exon 3 of the dopamine D4 receptor (DRD4) gene, and the other in the 3' untranslated region of the dopamine transporter (DAT1 or SCLA6A3) gene. It has been reported that allele frequencies of these polymorphisms varied between populations and this could affect the results in the association studies. Due to the previous findings, the objective of the present study was to determine the allele frequencies of DRD4 and DAT1 in an epidemiological sample of the adolescent population of México City. We found that the frequencies presented in our study were in between those reported for Caucasians and those reported for the American Indigenous population, this result are consistent with Euro-Indigenous inbreeding that has occurred in Mexico. Moreover, the results presented in the present study could explain the lack of consistency in the association analysis and make necessary to develop these investigations in our population.

Existe evidencia fehaciente de la influencia genética en los trastornos psiquiátricos y se ha propuesto que el sistema dopáminergico cerebral puede ser uno de los afectados en diversos trastornos como la esquizofrenia, el abuso de sustancias y el trastorno por déficit de atención e hiperactividad. En este sentido, los sistemas genéticos más estudiados son 2 VNTRs; uno localizado en el exón 3 del gen del Receptor a dopamina D4 (DRD4) y el otro en la región 3' no traducida del transportador a dopamina (DAT1 o SCL6A3). Se ha reportado que las frecuencias alélicas de estos polimorfismos difieren significativamente entre poblaciones y que esto puede afectar los resultados en los estudios de asociación. Debido a lo anterior, el objetivo del presente trabajo fue determinar las frecuencias alélicas del DRD4 y del DAT1 a partir de una muestra epidemiológica de la población adolescente de la Ciudad de México. Las frecuencias alélicas reportadas en el presente estudio son intermedias a las reportadas en caucásicos y poblaciones indígenas de América, lo que concuerda con la historia de mestizaje ocurrida en México. Estás diferencias pueden ayudar a explicar la falta de consistencia en diferentes estudios de asociación y hacen necesario realizarlos en población mexicana.

No Association between the Response to Methylphenidate and DRD4 Gene Polymorphism in Korean Attention Deficit Hyperactivity Disorder: A Case Control Study

OBJECTIVE: Recently the relationship between alleles frequency distribution, drug response and the attention deficit hyperactivity disorder (ADHD), has been actively researched. We investigated the association between the genetic type, alleles and drug response for the dopamine receptor D4 (DRD4) gene in ADHD patients in Korea. METHODS: One hundred fourteen patients diagnosed with ADHD according to the the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) diagnostic criteria were selected for the study. The clinical features of patients were confirmed by Korean version of Conners' parent rating scale, Attention deficit Diagnostic System, Korean version of Spielberger state-trait anxiety scale. Blood samples were taken from the 198 subjects. DNA was extracted from blood lymphocytes, PCR was performed for DRD4 Polymorphism. Alleles, genotype frequencies, the Clinical Global Impression (CGI) improvement score were compared using the chi-square test. Korean ADHD Rating Scale (K-ARS) and CGI severity scores were compared using the t-test. RESULTS: In comparing the ADHD with 4/4 repeats group and without the ADHD with 4/4 repeats group, no significant difference was seen between the DRD4 genetic type, alleles distribution, and CGI drug response. CONCLUSION: As a result, it is viewed that there is no relationship between ADHD and DRD4, but final decision is indefinite. Follow up studies with larger patient or pure subgroups are expected.

Efecto de la portación de alelos de riesgo de MAO-A y DRD4 sobre mediciones de agresión / Effect of Risk Alleles MAO-A and DRD4 on Aggression Measures

Entre los diversos factores asociados con la predisposición a la conducta violenta se encuentra la portación de alelos de riesgo. Para investigar el efecto de dos alelos de riesgo (baja actividad de MAO-A y 7 repeticiones DRD4) sobre mediciones de agresión, se evaluaron mediante escalas psicológicas a 60 hombres sanos. Los resultados indicaron que tanto el efecto principal de cada uno de los alelos de riesgo, como su interacción impactan sobre mediciones de hostilidad, enojo, impulsividad, empatía y rasgos antisociales de psicopatía. Se concluye que es necesario investigar el efecto de estos alelos sobre la estructura y función cerebrales, además estos alelos aparentemente confieren riesgo para el desarrollo de conductas violentas.

Among the factors associated with the predisposition to violent behavior is the bearing of risk alleles. To investigate the effect of two risk alleles (low activity of MAO-A and 7 repeat DRD4) 60 healthy men were assessed on psychological scales of aggression. The results indicated that both the main effect of each of the risk alleles, and their interaction impact on measures of hostility, anger, impulsivity, empathy and antisocial traits of psychopathy. We conclude that it is necessary to investigate the effect of these alleles on brain structure and function; these alleles apparently also confer risk for the development of violent behavior.

The Association among the Genetic Polymorphism of Dopamine D4 Receptor, Temperament and Alcohol Drinking Behavior in Young Korean Adults

OBJECTIVES: The aim of this study is to explore the association among DRD4 polymorphism, temperament and alcohol drinking behavior of Koreans in their early adulthood. METHOD: Participants were 172 healthy Korean adults (mean age 28.1 +/- 0.8). Their temperament was assessed with the Temperament and Character Inventory (TCI) and their alcohol drinking behavior were evaluated with a self-reported questionnaire including the CAGE and the Korean version of Alcohol Use Disorder Identification Test (AUDIT-K). DRD4 exon III 48 base pair variable number of tandem repeats (VNTR) was genotyped by PCR. RESULTS: No significant association was found between DRD4 polymorphism and TCI temperament dimension (novelty seeking, harm avoidance, reward dependence, and persistence) as well as alcohol drinking behavior scales. However, novelty seeking was significantly associated with alcohol drinking behavior. The higher level of novelty seeking was associated with the higher severity index of drinking (B = -0.225, p < 0.001) and problematic alcohol use on the CAGE and AUDIT-K [Odds Ratio (OR) = 1.111, 95% Confidence Interval (CI) 1.021-1.209, p = 0.015, OR = 1.087, 95% CI 1.009-1.170, p = 0.028]. CONCLUSION: In our study, while there is no significant association of DRD4 polymorphism with temperament and alcohol drinking behavior, novelty seeking affects problematic alcohol use. Results suggest that novelty seeking may play an important role in problematic alcohol use in young Korean adults.

Association of DRD4 Gene Polymorphism on Attention Deficit Hyperactivity Disorder: Preliminary Study / 대한정신약물학회지

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) has a strong genetic basis, and the relationship between the allele frequency distribution and ADHD has been researched actively. We investigated the association between the DRD4 genotype and ADHD patients in Korea, in comparison with case control and family based control groups. METHODS: The study enrolled 118 patients diagnosed with ADHD according to the DSM-IV diagnostic criteria and their parents (n = 70), and 84 normal children were recruited as controls. The clinical features of the patients were confirmed using the Korean versions of the Child Behavior Checklist (CBCL), Conners' parent rating scale, Attention Deficit Diagnostic System, and Spielberger state/trait anxiety scale. Blood samples were taken from the 272 subjects. DNA was extracted from blood lymphocytes. PCR was performed to examine DRD4 polymorphisms. Allele and genotype frequencies were compared using the Chi-square test for the casecontrol analysis and the transmission disequilibrium test (TDT) for the family-based analyses. RESULTS: In comparing the ADHD transmitted group with the not transmitted group, no significant differences were seen in the DRD4 genotype, allele distribution, or ADHD. CONCLUSION: However, there was a trend to an association between the DRD4 genotype, allele distribution, and ADHD for the case-control analysis. Follow-up studies with more patients or pure subgroups are needed.

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.

Dopamine receptor D4 exon 3 variable number of tandem repeat polymorphism: Distribution in eastern Indian population.

BACKGROUND: A 48bp variable number of tandem repeat (VNTR), in the dopamine receptor D4 (DRD4), has been extensively studied in association with a variety of traits and neuropsychiatric disorders in different ethnic groups; the VNTR has been found to affect receptor binding. AIMS: This investigation, for the first time, compared distribution of DRD4 VNTR in different Indian populations from the eastern part of the country, belonging to Indo-Caucasoid and Indo-Mongoloid ethnicity. MATERIALS AND METHODS: 852 individuals were recruited and divided into six population groups; Brahmin, Kayastha, Scheduled Caste, Mahishya, Muslim and Manipuri (Meitei). Allele and genotype frequencies were compared among groups as well as with data available for south-western Indian population. RESULTS: A total of six alleles (2-7-repeats) were observed, of which the 4-repeat (4R) was most frequent. Gross genetic dissimilarities were noticed between the Indo-Caucasoid and Indo-Mongoloid ethnic groups. Muslim group lacked 5R and 7R, while Manipuri group exhibited a very high frequency of 2R. Populations from eastern India revealed lower 7R frequencies as compared to the south-western populations. CONCLUSIONS: The DRD4 VNTR has been reported to play important role in cognition and alleles with higher repeats have been found to be associated with novelty seeking and personality traits. The present comparative analysis of different eastern Indian population would be helpful in extending our knowledge on this particular DRD4 variant. It will also be useful in understanding the behavioural differences between populations in the light of their genetic make up.

Association Study of Dopamine D2, D4 Receptor Gene, GABA(A) Receptor beta Subunit Gene, and Serotonin Transporter Gene Polymorphism with Children of Alcoholics in Korea: Preliminary Study / 신경정신의학

OBJECTIVES: The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A 1 allele of the dopamine receptor 2 gene (DRD2) may be associated with the negative affect and positive alcohol expectancy of the COAs. In addition, several researchers reported that COAs might be associated with the GABAA receptor beta subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR). In this study, we investigated the association of polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with COAs to examine the genetic risk factors of COAs. METHODS: Twenty-two COAs and 23 control children (children of non-Alcoholics ; Non-COAs) were included for the genetic study. All COAs aged 6 to 18 were recruited and selected from families of alcoholic patients in alcohol clinics of three university and mental hospital. Alcoholism of parents was classified as type I (non-antisocial, late onset) and type II (antisocial, early onset) by Cloninger's classification. The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. Chi-square method was used for evaluating the associations between genetic polymorphism and the COAs. RESULTS: The frequency of A1+ allele of DRD2 in COAs were significantly higher than Non-COAs (Chi-square=4.45, df=1, p=0.035). Significant association between the genotype of DRD4 and COAs was found (Chi-square=8.32, df=1, p=0.004). G1- alleles of GABRB3 in COAs were significantly higher than in Non-COAs (Chi-square=6.622, df=1, p=0.022). We found no association of the polymorphic alleles of 5-HTTLPR with the COAs (Chi-square=0.021, df=1, p=0.884). There were significant associations between the type of parental alcoholism and depression of COAs. CONCLUSION: We found that the children of alcoholics had significantly increased genetic risk of alcohol drinking expectancy. This study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology.

No Association of DRD4 Exon III Polymorphism with Attention-Deficit Hyperactivity Disorder in Korean Children Population

OBJECTIVES: The aim of the current study is to test for the association of DRD4 exon III VNTR polymorphism with attention-deficit hyperactivity disorder(ADHD) in Korean children population. METHODS: 113 Korean children with ADHD, 102 parents, and 133 control subjects participated with the current study. The distribution of genotypes and alleles of DRD4 exon III VNTR in children with ADHD was compared with that in control subjects. In addition, 69 children with ADHD and their parents were analyzed using the transmission disequilibrium test(TDT). RESULTS: We could not find any significant differences in the distribution of genotypes and alleles at DRD4 exon III VNTR polymorphism between children with ADHD and control subjects. In addition, there was no preferential transmission of long allele of DRD4 exon III VNTR polymorphism. CONCLUSION: These results suggest that DRD4 is not associated with ADHD in Korean children population.

El gen receptor a dopamina D4 y su asociación con los trastornos mentales / DRD4 polymorphysm and the association with mental disorders

The dopamine D4 receptor (DRD4) is the most important gene in psychiatric genetics since its involvement in the physiology of behavior, pharmacology response and psychopathology. DRD4's sequence gene present some polymorphism such as in the exon 3 constituted from 2 to 10 copies of repetitive sequences of 48 base pair (bp), from class variable number tandem repeats (VNTR). An additional genetic variant in the exon 1 presents polymorphisms to 12 bp VNTR, and the variation -521 C by T of the promoter region. The -521 T alíele can reduce the efficiency of the gene expression in comparison with the C alíele. The DRD4 gene codes a protein transmembranal of 7 domains, distributed in front cortex, striatum, hypothalamus and hippocampus. This review discusses the biological significance of DRD4 gene and its perspective with emphasis on the impact of association studies in some illness mental and behavioral traits. The DRD4 polymorphism has been studied in association with illnesses like schizophrenia, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive with tics, bipolar manic-depressive disorder, in addition behavioral traits such as novelty seeking. The DRD4 gene is a genetic marker that could play a role in etiology of different mental illness, and behavioral traits, and its polymorphism can be used in association studies, epigenetic and pharmacogenomic analysis for help to understand the genetics basis of both mental disorders and traits.

El gen receptor a dopamina D4 (DRD4) ha sido analizado por su estructura, su polimorfismo genético, su constitución proteínica, su distribución neuroanatómica y su respuesta farmacológica. La secuencia del gen DRD4 presenta varios polimorfismos, como del tipo número variable de repetidos en tándem (VNTR) en el exón 3, el VNTR de 12 pares de bases del exón 1 y el polimorfismo único de nucleótidos (SNP) de la región del promotor. El gen DRD4 codifica una proteína transmembranal de 7 dominios, que se distribuye en corteza frontal, en estriado, en hipotálamo y en el hipocampo. Esta revisión discute la importancia biológica del gen DRD4 y sus perspectivas ante nuevas áreas de investigación con énfasis en recientes estudios de asociación en diferentes enfermedades mentales y en comportamientos. El DRD4 es uno de los genes candidatos cuya variación polimórfica ha sido relacionada con algunos trastornos psiquiátricos como esquizofrenia, trastorno de déficit de atención e hiperactividad, obsesivo compulsivo con tics y trastorno por consumo de sustancias, así como con la característica de personalidad de búsqueda de la novedad. El gen DRD4 es un marcador genético y un modelo útil para estudios de asociación, epigenéticos y farmacogenómicos que buscan identificar el origen de trastornos psiquiátricos y comportamientos.

Association of Dopamine D4 Receptor Gene(DRD4) VNTR Polymorphism and Response to Methylphenidate Treatment in Korean ADHD Children / 신경정신의학

OBJECTIVES: In the present study, we investigate the association between homozygosity of the 4-repeat allele (4/4) at the DRD4 and the response to the treatment with MPH in Korean children with ADHD. METHODS: The present study included 71 children with ADHD (8.231.78 years) from two children's psychiatric clinics in South Korea. All drug-naive children with ADHD were treated with MPH for about 8 weeks. The subjects who showed improvement of over 50% compared with the baseline ARS score after 8 weeks of treatment were termed as the 'good response' group. The subjects who showed an improvement of less than 50% were considered as the 'poor response' group. After genotyping for DRD4 were performed, we investigated correlation between homozygosity for 4-repeat allele at DRD4 and the response to MPH treatment. RESULTS: We found that while 79.5% (31/39) of the subjects with homozygosity of 4-repeat allele at DRD4 showed good response to MPH treatment, 68.8% (22/32) of the subjects without homozygosity of 4-repeat allele at DRD4 showed poor response to MPH treatment according to ARS scores assessed by their parents (chi2=16.762, df=1, p<0.01). We also found that while 61.5% (24/39) of the subjects with homozygosity of4-repeat allele at DRD4 showed good response to MPH treatment, 87.5% (28/32) of the subjects without homozygosity of the 4-repeat allele at DRD4 showed poor response to MPH treatment according to ARS scores assessed by their teachers (chi2=17.698, df=1, p<0.01). CONCLUSION: Our findings support an association between the homozygosity of 4-repeat allele and a good response to MPH in ADHD of Koreans.

Association between Schizophrenia and the Genetic Polymorphism of DRD3, DRD4 and HTR2A / 대한진단검사의학회지

BACKGROUND: Dopamine and serotonin receptors are candidate genes for the genetic study of schizophrenia because of their implication in the pathophysiology and etiology of schizophrenia (serotonine- dopamin hypothesis). A population-based association study was performed between schizophrenics and normal controls to identify the susceptibility genes. METHODS: A total of 145 schizophrenics and 242 normal controls were recruited. Ser9Gly polymorphism of DRD3, 12 bp repeat of DRD4, and 102T/C of HTR2A were selected as candidate polymorphism. The molecular techniques such as polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-polyacrylamide gel electrophoresis were used. Chi-square analysis was performed to find any differences between two groups and logistic linear regression was tested to evaluate the interaction between three genes. RESULTS: There were no significant differences in allele frequencies and genotype frequencies of the three genetic polymorphism. Stratified by sex, the difference of DRD4 allele (P=0.065) and HTR2A allele (P=0.083) and genotype (P=0.054) was observed between male patients and controls; also noted was the difference of HTR2A genotype (P=0.080) between female patients and controls. Stratified by age of onset, the difference in the linear trend of DRD3 between early-onset patients and normal control (P=0.003) was observed. Stratified by family history, the difference in the linear trend of DRD4 (P=0.008) was also observed. Logistic linear regression with 90 patients who had early-onset phenotype (< or =20 year-old) or family history showed a significant result in interaction term (P=0.053). CONCLUSIONS: The finding that there were significant results only after stratification may imply a different genetic load on each subgroup of the disease. The interaction of genes between DRD3, DRD4, and HTR2A in a subgroup with supposedly high genetic background may support the serotonindopamine hypothesis. This, however, should be verified hereafter in large-scale studies.

Association between Dopamine Receptor D4 Polymorphisms and Novelty Seeking Personality Trait in a Korean Population / 신경정신의학

OBJECTIVES: We investigated the relationship of personality traits with dopamine D4 receptor(DRD4) exon III polymorphism in a Korean population. METHODS: We analysed DRD4 exon III 48-bp repeats polymorphism in 173 Korean healthy female adolescents(age=13.88+/-0.29 years) who also completed Temperament and Character Inventory(TCI). RESULTS: Novelty seeking score of the TCI was significantly higher in the subjects with DRD4 long alleles(>or=5 repeats) compared with the subjects without these(t=2.11, p=0.037). CONCLUSION: The present study supports the previous reports that long repeats of the DRD4-exon III polymorphism are related with Novelty Seeking personality.