There is extensive research focused on identifying predictors of autism, including biomarkers such as genes and neurophysiology. Because of inconsistent data, I explored these biomarkers as predictors of variability in behavioral outcomes (i.e., internalizing and externalizing symptoms), rather than indicators of the disorder per se. In a sample of children (ages 8-16) diagnosed with High Functioning Autism (HFA) and an age- and IQ- matched typically developing comparison group, individual differences in behavioral outcomes were assessed in relation to common genetic polymorphisms, 5-HTTLPR and DRD4, and neurophysiological (ERN) and behavioral (rate of self-correction) measures of response monitoring. Although the diagnostic groups did not differ on allele frequency for 5-HTTLPR, carriers of the L variant displayed attenuated ERN amplitudes at frontal-central sites, lower rates of self-correction following errors, and higher levels of parent-reported Somatization and Hyperactivity. With respect to DRD4, an overrepresentation of the 7-repeat allele was found in the HFA sample. Regardless of diagnostic group, 7-repeat allele carriers were rated as having more attention problems. These results suggest that genetics and neural correlates of response monitoring may explain interindividual variations in social emotional functioning of both HFA and typically developing children alike. However, contrary to hypothesis, response monitoring did not mediate the association between 5-HTTLPR or DRD4 and outcome measures. Future directions of this research may look at how genes and measures of response monitoring affect etiology, course, and treatment of autism and other related disorders.

Previous research has shown a large genetic influence over personality traits, especially sensation seeking. One gene thought to influence this behavioural trait is the dopamine-4-receptor gene (DRD4), in which variants have been associated with sensation seeking and novelty seeking in some, but not all studies. The inconsistencies between studies may be due to heterogeneity in both the behaviours and the populations being assessed. Some studies included only males and few studies have a priori analyzed males and females separately. SS has been associated with high-risk sports, including skiing; however, this is the first study to address the possibility that genetics may play a role in individuals’ inclination towards SS in sport. Using the Contextual Sensation Seeking Questionnaire for Skiing (CSSQ-S), developed and validated for this study, and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), levels of SS in males and females were analyzed in association with the alleles of a polymorphism in the dopamine-4-receptor, -521 C/T (a C or a T at position -521). Behavioural analysis of skiers (N = 200) revealed a significant correlation (r²= .506, p < .001) between skier behaviour (CSSQ-S) and skier personality score (ZKPQ) for sensation seeking. Genotype analysis (N = 74) revealed allele frequencies of .58 C and .42 T and an over-representation of the C allele was found in the population of skiers compared with a general Caucasian population (p < .01). In females, a significant association was found between the homozygous C/C genotype and high levels of contextual skiing SS behaviour (N = 36, p = .006, η² = .2), along with a non-significant trend between ZKPQ impulsive SS scores and the alleles of -521 C/T (p = .086). No association, however, was found in males (N=38, p ZKPQ = .473, p CSSQ-S = .345). This study supports the hypothesis that alleles of the DRD4 -521 C/T polymorphism are associated with context-specific SS behaviours, however only in females. Social pressures may differentially influence male and female sensation-seeking behaviour which may explain the lack of association in males, though this hypothesis requires further investigation.

Previous research has shown a large genetic influence over personality traits, especially sensation seeking. One gene thought to influence this behavioural trait is the dopamine-4-receptor gene (DRD4), in which variants have been associated with sensation seeking and novelty seeking in some, but not all studies. The inconsistencies between studies may be due to heterogeneity in both the behaviours and the populations being assessed. Some studies included only males and few studies have a priori analyzed males and females separately. SS has been associated with high-risk sports, including skiing; however, this is the first study to address the possibility that genetics may play a role in individuals’ inclination towards SS in sport. Using the Contextual Sensation Seeking Questionnaire for Skiing (CSSQ-S), developed and validated for this study, and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), levels of SS in males and females were analyzed in association with the alleles of a polymorphism in the dopamine-4-receptor, -521 C/T (a C or a T at position -521). Behavioural analysis of skiers (N = 200) revealed a significant correlation (r²= .506, p < .001) between skier behaviour (CSSQ-S) and skier personality score (ZKPQ) for sensation seeking. Genotype analysis (N = 74) revealed allele frequencies of .58 C and .42 T and an over-representation of the C allele was found in the population of skiers compared with a general Caucasian population (p < .01). In females, a significant association was found between the homozygous C/C genotype and high levels of contextual skiing SS behaviour (N = 36, p = .006, η² = .2), along with a non-significant trend between ZKPQ impulsive SS scores and the alleles of -521 C/T (p = .086). No association, however, was found in males (N=38, p ZKPQ = .473, p CSSQ-S = .345). This study supports the hypothesis that alleles of the DRD4 -521 C/T polymorphism are associated with context-specific SS behaviours, however only in females. Social pressures may differentially influence male and female sensation-seeking behaviour which may explain the lack of association in males, though this hypothesis requires further investigation.

Previous research has shown a large genetic influence over personality traits, especially sensation seeking. One gene thought to influence this behavioural trait is the dopamine-4-receptor gene (DRD4), in which variants have been associated with sensation seeking and novelty seeking in some, but not all studies. The inconsistencies between studies may be due to heterogeneity in both the behaviours and the populations being assessed. Some studies included only males and few studies have a priori analyzed males and females separately. SS has been associated with high-risk sports, including skiing; however, this is the first study to address the possibility that genetics may play a role in individuals’ inclination towards SS in sport. Using the Contextual Sensation Seeking Questionnaire for Skiing (CSSQ-S), developed and validated for this study, and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), levels of SS in males and females were analyzed in association with the alleles of a polymorphism in the dopamine-4-receptor, -521 C/T (a C or a T at position -521). Behavioural analysis of skiers (N = 200) revealed a significant correlation (r²= .506, p < .001) between skier behaviour (CSSQ-S) and skier personality score (ZKPQ) for sensation seeking. Genotype analysis (N = 74) revealed allele frequencies of .58 C and .42 T and an over-representation of the C allele was found in the population of skiers compared with a general Caucasian population (p < .01). In females, a significant association was found between the homozygous C/C genotype and high levels of contextual skiing SS behaviour (N = 36, p = .006, η² = .2), along with a non-significant trend between ZKPQ impulsive SS scores and the alleles of -521 C/T (p = .086). No association, however, was found in males (N=38, p ZKPQ = .473, p CSSQ-S = .345). This study supports the hypothesis that alleles of the DRD4 -521 C/T polymorphism are associated with context-specific SS behaviours, however only in females. Social pressures may differentially influence male and female sensation-seeking behaviour which may explain the lack of association in males, though this hypothesis requires further investigation. / Education, Faculty of / Kinesiology, School of / Graduate

This study examined the role of birth complications, delinquent peers and siblings, and specific dopamine receptors on the development of externalizing behavior in children and adolescents, along with the role of heritability in aggression and delinquency. Specifically, it was hypothesized that increased birth complications, presence of specific dopamine receptor (DRD2 and DRD4) risk alleles, and delinquent peers or siblings would be related to increased externalizing behavior at follow-up. The sample consisted of 65 twin pairs, aged six to 16 (mean age = 9.06 years) who originally participated in the Southern Illinois Twins and Siblings Study (SITSS) at age five. Significant results were found for the stability of aggression from age five to follow-up and heritability of parent-rated aggression and delinquency measures was shown. Presence of delinquent peers or siblings was positively related to aggressive and delinquent behavior. Those with more delinquent peers and with the DRD2 risk allele were rated as more delinquent. In contrast, those without the DRD4 risk allele were also rated as more delinquent. Presence of birth complications was positively related to aggressive and delinquent behavior ratings by parents at follow-up. However, birth complications were negatively related to delinquency on youth-rated measures. Finally, those with fewer complications and more delinquent siblings engaged in more reported delinquent behavior. The present study provided important information concerning the effects of birth complications, delinquent peers and siblings, and specific dopamine receptors on the development of externalizing behavior in children and adolescents, along with the role of heritability in aggression and delinquency.

No description available.

O transtorno de déficit de atenção e hiperatividade (TDAH) é um dos transtornos psiquiátricos mais freqüentes da infância e adolescência, sendo caracterizado por sintomas de desatenção, hiperatividade e impulsividade. A contribuição genética na etiologia do TDAH é uma das mais altas já verificadas para transtornos psiquiátricos, com herdabilidade média estimada de 76%. Dentre os fatores genéticos que contribuiriam para o desenvolvimento da doença, genes que codificam componentes do sistema dopaminérgico estão entre os principais candidatos. Entre estes, o gene que codifica o receptor D4 de dopamina (DRD4) é o loco mais intensamente investigado nos estudos moleculares com o TDAH. O polimorfismo mais estudado no DRD4 é um VNTR de 48 pb localizado no exon 3; porém outros polimorfismos, localizados na região promotora do gene – uma duplicação de 120pb e os SNPs -521C>T e - 616C>G – também vêm sendo propostos como polimorfismos de suscetibilidade ao TDAH. Além desses, novas variantes em regiões regulatórias do gene, os SNPs rs11246227 e rs11246228, foram observados recentemente em associação com sintomas de desatenção do TDAH. O objetivo geral do presente trabalho foi aumentar a compreensão acerca da participação do gene DRD4 na etiologia do TDAH na nossa população Para tanto, foi testada inicialmente a possibilidade de associação do SNP rs11246227, sendo em seguida investigado o significado funcional dos SNPs rs11246227 e rs11246228, e sua possível relação com a doença, através de ferramentas de bioinformática. O estudo de associação foi realizado em uma amostra composta por 478 pacientes com TDAH, diagnosticados segundo os critérios do DSM-IV, e seus pais biológicos. O rs112466227 foi investigado por abordagens baseada em família (FBAT) e dimensional (PBAT, ANOVA). A possibilidade de desequilíbrio de ligação (DL) com polimorfismos previamente investigados na presente amostra foi estimada pelo programa MLocus. A análise in silico foi realizada utilizando diferentes bases de dados genômicos e programas de predição de sítios alvo para miRNAs e de funcionalidade. A análise pelo FBAT mostrou um desvio significativo da transmissão do alelo C nos pacientes do subtipo desatento. Foram observadas evidências de DL com a duplicação de 120bp e com o VNTR do exon 3. As análises de bioinformática mostraram que os SNPs rs11246227 e rs11246228 estão localizadas na região 3’ do gene DRD4, e não na região 5’, como previamente descrito. Diferenças entre os alelos, com perda ou ganho de sítios de ligação para diferentes miRNAs, foram detectados em ambos os SNPs pelos programas MicroInspector, 5 smiRNAdb e miRecords, e apenas no rs11246227 pelos programas Human miRNA Target e Mirò. A grande variabilidade e a complexidade genética marcante do gene DRD4 aliada à heterogeneidade fenotípica do TDAH provavelmente contribuíram para nossos resultados de associação, divergentes dos descritos na literatura, os quais necessitam de replicação em estudos futuros. Nossos achados em bioinformática sugerem um possível envolvimento dos SNPs investigados com a ligação de miRNAs relacionados aos processos de neurogênese e neuroplasticidade. Genes envolvidos com estes processos vêm sendo identificados nos genome-wide association studies realizados com o TDAH, o que apóia nossos resultados in silico. Entretanto, mais estudos funcionais são necessários, tanto in silico como in vitro, para esclarecer o envolvimento dos polimorfismos analisados na regulação da expressão do gene DRD4 via miRNAs e, consequentemente, do possível efeito desses elementos na etiologia da doença. / Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood and adolescence, characterized by inattentive, hyperactive and impulsive symptoms. Genetic contribution to ADHD etiology is one of the highest ever recorded for psychiatric disorders, with a mean heritability of 76%. Among genetic factors that could contribute to disorder development, genes encoding components from dopaminergic system are the main candidate. Of these, the dopamine D4 receptor gene (DRD4) is the most extensively investigated locus in molecular studies of ADHD. The most studied polymorphism in DRD4 gene is a variable number of tandem repeats (VNTR) of 48bp, located at exon 3, although other polymorphisms, located in promoter region – a 120bp duplication and the SNPs -521C> T and-616C> G – have also been proposed as susceptibility polymorphisms for ADHD. In addition, new variants in regulatory regions, the SNPs rs11246227 and rs11246228, have recently been associated with inattentive symptoms of the disorder. The overall objective of this study was to increase the understanding on the involvement of DRD4 gene in ADHD etiology in our population For this purpose, the possibility of association with the SNP rs11246227 was initially tested, being afterwards investigated the functional effect of both rs11246227 and rs11246228 and their possible relation to ADHD through bioinformatics approach. The association study was performed in a sample composed by 478 ADHD patients, diagnosed according to DSM-IV criteria, and their biological parents. The rs112466227 was investigated by both family-based (FBAT) and dimensional (PBAT, ANOVA) approaches. The possibility of linkage disequilibrium (LD) with polymorphisms previously investigated in the present sample was estimated by MLocus software. In silico analysis was conducted using different genomic databases and programs to predict miRNA target sites and functionality. FBAT analysis showed a significant excess of C allele transmission in inattentive subtype patients. Evidences of LD with both 120bp tandem duplication and exon 3 VNTR were observed. Bioinformatics analyses showed that both SNPs rs11246227 and rs11246228 are located in the 3' region of DRD4 gene, and not at 5’ region, as previously described. Differences between alleles, with loss or gain of binding sites, were detected in both SNPs by MicroInspector, smiRNAdb and miRecords, and only in rs11246227 by Human miRNA Targets and miRò DRD4 huge variability and marked genetic complexity allied to ADHD phenotypic heterogeneity might have contributed to our 7 association results, distinct from the ones reported in literature, what needs to be replicated in future studies. Our bioinformatics findings suggest a possible involvement of investigated SNPs in binding properties of miRNAs related to processes of neurogenesis and neuronal plasticity. Genes involved in these processes have been identified in ADHD genome-wide association studies, reinforcing our in silico results. However, new functional studies, using both in silico and in vitro approaches, are needed to clarify the involvement of the investigated polymorphisms in DRD4 expression control mediated by miRNAs and, consequently, the possible effect of these elements in ADHD etiology.

O transtorno de déficit de atenção e hiperatividade (TDAH) é um dos transtornos psiquiátricos mais freqüentes da infância e adolescência, sendo caracterizado por sintomas de desatenção, hiperatividade e impulsividade. A contribuição genética na etiologia do TDAH é uma das mais altas já verificadas para transtornos psiquiátricos, com herdabilidade média estimada de 76%. Dentre os fatores genéticos que contribuiriam para o desenvolvimento da doença, genes que codificam componentes do sistema dopaminérgico estão entre os principais candidatos. Entre estes, o gene que codifica o receptor D4 de dopamina (DRD4) é o loco mais intensamente investigado nos estudos moleculares com o TDAH. O polimorfismo mais estudado no DRD4 é um VNTR de 48 pb localizado no exon 3; porém outros polimorfismos, localizados na região promotora do gene – uma duplicação de 120pb e os SNPs -521C>T e - 616C>G – também vêm sendo propostos como polimorfismos de suscetibilidade ao TDAH. Além desses, novas variantes em regiões regulatórias do gene, os SNPs rs11246227 e rs11246228, foram observados recentemente em associação com sintomas de desatenção do TDAH. O objetivo geral do presente trabalho foi aumentar a compreensão acerca da participação do gene DRD4 na etiologia do TDAH na nossa população Para tanto, foi testada inicialmente a possibilidade de associação do SNP rs11246227, sendo em seguida investigado o significado funcional dos SNPs rs11246227 e rs11246228, e sua possível relação com a doença, através de ferramentas de bioinformática. O estudo de associação foi realizado em uma amostra composta por 478 pacientes com TDAH, diagnosticados segundo os critérios do DSM-IV, e seus pais biológicos. O rs112466227 foi investigado por abordagens baseada em família (FBAT) e dimensional (PBAT, ANOVA). A possibilidade de desequilíbrio de ligação (DL) com polimorfismos previamente investigados na presente amostra foi estimada pelo programa MLocus. A análise in silico foi realizada utilizando diferentes bases de dados genômicos e programas de predição de sítios alvo para miRNAs e de funcionalidade. A análise pelo FBAT mostrou um desvio significativo da transmissão do alelo C nos pacientes do subtipo desatento. Foram observadas evidências de DL com a duplicação de 120bp e com o VNTR do exon 3. As análises de bioinformática mostraram que os SNPs rs11246227 e rs11246228 estão localizadas na região 3’ do gene DRD4, e não na região 5’, como previamente descrito. Diferenças entre os alelos, com perda ou ganho de sítios de ligação para diferentes miRNAs, foram detectados em ambos os SNPs pelos programas MicroInspector, 5 smiRNAdb e miRecords, e apenas no rs11246227 pelos programas Human miRNA Target e Mirò. A grande variabilidade e a complexidade genética marcante do gene DRD4 aliada à heterogeneidade fenotípica do TDAH provavelmente contribuíram para nossos resultados de associação, divergentes dos descritos na literatura, os quais necessitam de replicação em estudos futuros. Nossos achados em bioinformática sugerem um possível envolvimento dos SNPs investigados com a ligação de miRNAs relacionados aos processos de neurogênese e neuroplasticidade. Genes envolvidos com estes processos vêm sendo identificados nos genome-wide association studies realizados com o TDAH, o que apóia nossos resultados in silico. Entretanto, mais estudos funcionais são necessários, tanto in silico como in vitro, para esclarecer o envolvimento dos polimorfismos analisados na regulação da expressão do gene DRD4 via miRNAs e, consequentemente, do possível efeito desses elementos na etiologia da doença. / Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood and adolescence, characterized by inattentive, hyperactive and impulsive symptoms. Genetic contribution to ADHD etiology is one of the highest ever recorded for psychiatric disorders, with a mean heritability of 76%. Among genetic factors that could contribute to disorder development, genes encoding components from dopaminergic system are the main candidate. Of these, the dopamine D4 receptor gene (DRD4) is the most extensively investigated locus in molecular studies of ADHD. The most studied polymorphism in DRD4 gene is a variable number of tandem repeats (VNTR) of 48bp, located at exon 3, although other polymorphisms, located in promoter region – a 120bp duplication and the SNPs -521C> T and-616C> G – have also been proposed as susceptibility polymorphisms for ADHD. In addition, new variants in regulatory regions, the SNPs rs11246227 and rs11246228, have recently been associated with inattentive symptoms of the disorder. The overall objective of this study was to increase the understanding on the involvement of DRD4 gene in ADHD etiology in our population For this purpose, the possibility of association with the SNP rs11246227 was initially tested, being afterwards investigated the functional effect of both rs11246227 and rs11246228 and their possible relation to ADHD through bioinformatics approach. The association study was performed in a sample composed by 478 ADHD patients, diagnosed according to DSM-IV criteria, and their biological parents. The rs112466227 was investigated by both family-based (FBAT) and dimensional (PBAT, ANOVA) approaches. The possibility of linkage disequilibrium (LD) with polymorphisms previously investigated in the present sample was estimated by MLocus software. In silico analysis was conducted using different genomic databases and programs to predict miRNA target sites and functionality. FBAT analysis showed a significant excess of C allele transmission in inattentive subtype patients. Evidences of LD with both 120bp tandem duplication and exon 3 VNTR were observed. Bioinformatics analyses showed that both SNPs rs11246227 and rs11246228 are located in the 3' region of DRD4 gene, and not at 5’ region, as previously described. Differences between alleles, with loss or gain of binding sites, were detected in both SNPs by MicroInspector, smiRNAdb and miRecords, and only in rs11246227 by Human miRNA Targets and miRò DRD4 huge variability and marked genetic complexity allied to ADHD phenotypic heterogeneity might have contributed to our 7 association results, distinct from the ones reported in literature, what needs to be replicated in future studies. Our bioinformatics findings suggest a possible involvement of investigated SNPs in binding properties of miRNAs related to processes of neurogenesis and neuronal plasticity. Genes involved in these processes have been identified in ADHD genome-wide association studies, reinforcing our in silico results. However, new functional studies, using both in silico and in vitro approaches, are needed to clarify the involvement of the investigated polymorphisms in DRD4 expression control mediated by miRNAs and, consequently, the possible effect of these elements in ADHD etiology.

This study examined possible interactions between DRD4 genotype and parenting on children’s externalizing, internalizing, and prosocial behaviors, and explored both parent and child perceptions of all variables. Both diathesis-stress and differential susceptibility hypotheses were assessed for examining possible interactions for children with the DRD4 7-repeat allele. Data were collected from 58 families within the Southern Illinois Twins/Triplets and Siblings Study (SITSS). Results indicated that although no gene-environment interactions were found when examining child perceptions, a significant interaction emerged between DRD4 and parenting in predicting externalizing behaviors when using parent reports. Children without the 7-repeat allele appeared to be malleable to both positive and negative parenting, supporting differential susceptibility. Also, child and parent reports of parenting were both predictive of child behavior. Lastly, MZ twins perceived more similar parenting environments than DZ twins, and there appeared to be a stronger environmental effect of parenting on externalizing after controlling for the effects of genes. This study adds to the differential susceptibility literature and points to the importance of considering perceptions of both children and parents when examining the effects of parenting on child behaviors.

O transtorno de déficit de atenção e hiperatividade (TDAH) é um dos transtornos psiquiátricos mais freqüentes da infância e adolescência, sendo caracterizado por sintomas de desatenção, hiperatividade e impulsividade. A contribuição genética na etiologia do TDAH é uma das mais altas já verificadas para transtornos psiquiátricos, com herdabilidade média estimada de 76%. Dentre os fatores genéticos que contribuiriam para o desenvolvimento da doença, genes que codificam componentes do sistema dopaminérgico estão entre os principais candidatos. Entre estes, o gene que codifica o receptor D4 de dopamina (DRD4) é o loco mais intensamente investigado nos estudos moleculares com o TDAH. O polimorfismo mais estudado no DRD4 é um VNTR de 48 pb localizado no exon 3; porém outros polimorfismos, localizados na região promotora do gene – uma duplicação de 120pb e os SNPs -521C>T e - 616C>G – também vêm sendo propostos como polimorfismos de suscetibilidade ao TDAH. Além desses, novas variantes em regiões regulatórias do gene, os SNPs rs11246227 e rs11246228, foram observados recentemente em associação com sintomas de desatenção do TDAH. O objetivo geral do presente trabalho foi aumentar a compreensão acerca da participação do gene DRD4 na etiologia do TDAH na nossa população Para tanto, foi testada inicialmente a possibilidade de associação do SNP rs11246227, sendo em seguida investigado o significado funcional dos SNPs rs11246227 e rs11246228, e sua possível relação com a doença, através de ferramentas de bioinformática. O estudo de associação foi realizado em uma amostra composta por 478 pacientes com TDAH, diagnosticados segundo os critérios do DSM-IV, e seus pais biológicos. O rs112466227 foi investigado por abordagens baseada em família (FBAT) e dimensional (PBAT, ANOVA). A possibilidade de desequilíbrio de ligação (DL) com polimorfismos previamente investigados na presente amostra foi estimada pelo programa MLocus. A análise in silico foi realizada utilizando diferentes bases de dados genômicos e programas de predição de sítios alvo para miRNAs e de funcionalidade. A análise pelo FBAT mostrou um desvio significativo da transmissão do alelo C nos pacientes do subtipo desatento. Foram observadas evidências de DL com a duplicação de 120bp e com o VNTR do exon 3. As análises de bioinformática mostraram que os SNPs rs11246227 e rs11246228 estão localizadas na região 3’ do gene DRD4, e não na região 5’, como previamente descrito. Diferenças entre os alelos, com perda ou ganho de sítios de ligação para diferentes miRNAs, foram detectados em ambos os SNPs pelos programas MicroInspector, 5 smiRNAdb e miRecords, e apenas no rs11246227 pelos programas Human miRNA Target e Mirò. A grande variabilidade e a complexidade genética marcante do gene DRD4 aliada à heterogeneidade fenotípica do TDAH provavelmente contribuíram para nossos resultados de associação, divergentes dos descritos na literatura, os quais necessitam de replicação em estudos futuros. Nossos achados em bioinformática sugerem um possível envolvimento dos SNPs investigados com a ligação de miRNAs relacionados aos processos de neurogênese e neuroplasticidade. Genes envolvidos com estes processos vêm sendo identificados nos genome-wide association studies realizados com o TDAH, o que apóia nossos resultados in silico. Entretanto, mais estudos funcionais são necessários, tanto in silico como in vitro, para esclarecer o envolvimento dos polimorfismos analisados na regulação da expressão do gene DRD4 via miRNAs e, consequentemente, do possível efeito desses elementos na etiologia da doença. / Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood and adolescence, characterized by inattentive, hyperactive and impulsive symptoms. Genetic contribution to ADHD etiology is one of the highest ever recorded for psychiatric disorders, with a mean heritability of 76%. Among genetic factors that could contribute to disorder development, genes encoding components from dopaminergic system are the main candidate. Of these, the dopamine D4 receptor gene (DRD4) is the most extensively investigated locus in molecular studies of ADHD. The most studied polymorphism in DRD4 gene is a variable number of tandem repeats (VNTR) of 48bp, located at exon 3, although other polymorphisms, located in promoter region – a 120bp duplication and the SNPs -521C> T and-616C> G – have also been proposed as susceptibility polymorphisms for ADHD. In addition, new variants in regulatory regions, the SNPs rs11246227 and rs11246228, have recently been associated with inattentive symptoms of the disorder. The overall objective of this study was to increase the understanding on the involvement of DRD4 gene in ADHD etiology in our population For this purpose, the possibility of association with the SNP rs11246227 was initially tested, being afterwards investigated the functional effect of both rs11246227 and rs11246228 and their possible relation to ADHD through bioinformatics approach. The association study was performed in a sample composed by 478 ADHD patients, diagnosed according to DSM-IV criteria, and their biological parents. The rs112466227 was investigated by both family-based (FBAT) and dimensional (PBAT, ANOVA) approaches. The possibility of linkage disequilibrium (LD) with polymorphisms previously investigated in the present sample was estimated by MLocus software. In silico analysis was conducted using different genomic databases and programs to predict miRNA target sites and functionality. FBAT analysis showed a significant excess of C allele transmission in inattentive subtype patients. Evidences of LD with both 120bp tandem duplication and exon 3 VNTR were observed. Bioinformatics analyses showed that both SNPs rs11246227 and rs11246228 are located in the 3' region of DRD4 gene, and not at 5’ region, as previously described. Differences between alleles, with loss or gain of binding sites, were detected in both SNPs by MicroInspector, smiRNAdb and miRecords, and only in rs11246227 by Human miRNA Targets and miRò DRD4 huge variability and marked genetic complexity allied to ADHD phenotypic heterogeneity might have contributed to our 7 association results, distinct from the ones reported in literature, what needs to be replicated in future studies. Our bioinformatics findings suggest a possible involvement of investigated SNPs in binding properties of miRNAs related to processes of neurogenesis and neuronal plasticity. Genes involved in these processes have been identified in ADHD genome-wide association studies, reinforcing our in silico results. However, new functional studies, using both in silico and in vitro approaches, are needed to clarify the involvement of the investigated polymorphisms in DRD4 expression control mediated by miRNAs and, consequently, the possible effect of these elements in ADHD etiology.