Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention

An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit/hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.

Absence of the 7-repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls

Many genetic studies have demonstrated an association between the 7-repeat (7r) allele of a 48-base pair variable number of tandem repeats (VNTR) in exon 3 of the DRD4 gene and the phenotype of attention deficit hyperactivity disorder (ADHD). Previous studies have shown inconsistent associations between the 7r allele and neurocognitive performance in children with ADHD. We investigated the performance of 128 children with and without ADHD on the Fixed and Random versions of the Sustained Attention to Response Task (SART). We employed timeseries analyses of reaction-time data to allow a fine-grained analysis of reaction time variability, a candidate endophenotype for ADHD. Children were grouped into either the 7r-present group (possessing at least one copy of the 7r allele) or the 7r-absent group. The ADHD group made significantly more commission errors and was significantly more variable in RT in terms of fast moment-to-moment variability than the control group, but no effect of genotype was found on these measures. Children with ADHD without the 7r allele made significantly more omission errors, were significantly more variable in the slow frequency domain and showed less sensitivity to the signal (d') than those children with ADHD the 7r and control children with or without the 7r. These results highlight the utility of time-series analyses of reaction time data for delineating the neuropsychological deficits associated with ADHD and the DRD4 VNTR. Absence of the 7-repeat allele in children with ADHD is associated with a neurocognitive profile of drifting sustained attention that gives rise to variable and inconsistent performance. (c) 2008 Wiley-Liss, Inc.

Modeling gene-environment interaction in longitudinal data : risk for neuroticism due to interaction between maternal care and the Dopamine 4 Receptor gene (DRD4)

The purpose of this study was to investigate risk for neuroticism due to the joint action of low maternal care and compromised mesocorticolimbic ‘reward’ system function linked to a variable number tandem repeat (VNTR) in the dopamine 4 receptor gene (DRD4). Data were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of 2,000 young Australians followed from adolescence to young adulthood across 8 waves from 14- to 28-years. Genetic risk was defined by carriage of at least one copy of the 7-repeat allele or derivative alleles 5, 6, and 8 (labeled 7R+). Neuroticism was assessed in adolescence and young adulthood. We observed an approximately fourfold increase in the odds of reporting neurotic symptoms in carriers of the 7R+ disposition who reported low maternal care compared with non-carriers who reported high maternal care. The percentage of risk attributable to mechanisms in which both factors played a role was 35%. Findings are discussed in terms of implications for prevention.

A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism

Introduction: Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+.

Methods: Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14–24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants.

Results: While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers.

Conclusions: Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.

Dopamine receptor D4 polymorphism predicts the effect of L-DOPA on gambling behavior

BACKGROUND There is ample evidence that a subgroup of Parkinson's disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling. The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors. These are potentially of genetic origin, since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 (DRD4) gene. Using a pharmacogenetic approach, we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects. METHODS We administered 300 mg of L-dihydroxyphenylalanine (L-DOPA) or placebo to 200 healthy male subjects who were all genotyped for their DRD4 polymorphism. Subjects played a gambling task 60 minutes after L-DOPA administration. RESULTS Without considering genetic information, L-DOPA administration did not lead to an increase in gambling propensity compared with placebo. As expected, however, an individual's DRD4 polymorphism accounted for variation in gambling behavior after the administration of L-DOPA. Subjects who carry at least one copy of the 7-repeat allele showed an increased gambling propensity after dopaminergic stimulation. CONCLUSIONS These findings demonstrate that genetic variation in the DRD4 gene determines an individual's gambling behavior in response to a dopaminergic drug challenge. They may have implications for the treatment of Parkinson's disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior.

Effects of dopamine receptor D4 variation on alcohol and tobacco use and on novelty seeking: Multivariate linkage and association analysis

The dopamine D4 receptor gene contains a polymorphic sequence consisting of a variable number of 48-base-pair (bp) repeats, and there have been a number of reports that this polymorphism is associated with variation in novelty seeking or in substance abuse and addictive behaviors. In this study we have assessed the linkage and association of DRD4 genotype with novelty seeking, alcohol use, and smoking in a sample of 377 dizygotic twin pairs and 15 single twins recruited from the Australian Twin Registry (ATR). We found no evidence of linkage or association of the DRD4 locus with any of the phenotypes. We made use of repeated measures for some phenotypes to increase power by multivariate genetic analysis, but allelic effects were still non-significant. Specifically, it has been suggested that the DRD4 7-repeat allele is associated with increased novelty seeking in males but we found no evidence for this, despite considerable power to do so. We conclude that DRD4 variation does not have an effect on use of alcohol and the problems that arise from it, on smoking, or on novelty seeking behavior. (C) 2003 Wiley-Liss, Inc.

The policy and ethical implications of genetic research on attention deficit hyperactivity disorder

Objective: To review the policy and ethical implications of recent research on the molecular genetics of attention deficit hyperactivity disorder (ADHD). Method: MEDLINE and psycINFO database searches were used to identify studies on the genetics of ADHD. The implications of replicated candidate genes are discussed. Results: The findings for most genes have been inconsistent but several studies have implicated the genes in the dopaminergic pathway in the aetiology of ADHD. Conclusions: The current evidence on the genetics of ADHD is insufficient to justify genetic screening tests but it will provide important clues as to the aetiology of ADHD. Genetic information on susceptibility to ADHD has the potential to be abused and to stigmatize individuals. Researchers and clinicians need to be mindful of these issues in interpreting and disseminating the results of genetic studies of ADHD.

Molecular Genetics of Schizophrenia and Related Intermediate Phenotypes in a Founder Population

Schizophrenia, affecting about 1% of population worldwide, is a severe mental disorder characterized by positive and negative symptoms, such as psychosis and anhedonia, as well as cognitive deficits. At present, schizophrenia is considered a complex disorder of neurodevelopmental origin with both genetic and environmental factors contributing to its onset. Although a number of candidate genes for schizophrenia have been highlighted, only very few schizophrenia patients are likely to share identical genetic liability. This study is based on the nation-wide schizophrenia family sample of the National Institute for Health and Welfare, and represents one of the largest and most well-characterized familial series in the world. In the first part of this study, we investigated the roles of the DTNBP1, NRG1, and AKT1 genes in the background of schizophrenia in Finland. Although these genes are associated with schizophrenia liability in several populations, any significant association with clinical diagnostic information of schizophrenia remained absent in our sample of 441 schizophrenia families. In the second part of this study, we first replicated schizophrenia linkage on the long arm of chromosome 7 in 352 schizophrenia families. In the following association analysis, we utilized additional clinical disorder features and intermediate phenotypes – endophenotypes - in addition to diagnostic information from altogether 290 neuropsychologically assessed schizophrenia families. An intragenic short tandem repeat allele of the regional RELN gene, supposed to play a role in the background of several neurodevelopmental disorders, showed significant association with poorer cognitive functioning and more severe schizophrenia symptoms. Additionally, this risk allele was significantly more prevalent among the individuals affected with schizophrenia spectrum disorders. We have previously identified linkage of schizophrenia and its cognitive endophenotypes on the long arms of chromosomes 2, 4, and 5. In the last part of this study, we selected altogether 104 functionally relevant candidate genes from the linked regions. We detected several promising associations, of which especially interesting are the ERBB4 gene, showing association with the severity of schizophrenia symptoms and impairments in traits related to verbal abilities, and the GRIA1 gene, showing association with the severity of schizophrenia symptoms. Our results extend the previous evidence that the genetic risk for schizophrenia is at least partially mediated via the effects of the candidate genes and their combinations on relevant brain systems, resulting in alterations in different disorder domains, such as the cognitive deficits.

Estudio de asociación entre genotipo de DAT1 y transtorno por déficit de atención / hiperactividad

Introducción: El TDAH tiene un componente genético importante; el gen de transportador de Dopamina (DAT1) se ha asociado con susceptibilidad al TDAH y con sus endofenotipos. El VNTR de 40pb en la región 3’UTR aumenta la expresión del DAT1. En Colombia no hay ningún estudio previo que indique evidencia de la asociación genética entre TDAH y el gen DAT1. Objetivo: Determinar asociación entre el VNTR del DAT1 y el fenotipo y/o endofenotipos del TDAH. Métodos: Se seleccionaron 73 pacientes con TDAH y 75 controles, se valoró en los casos inteligencia y funciones ejecutivas. Mediante (PCR) se amplificó el VNTR DAT1. Se establecieron estadísticos genético poblacionales, análisis de asociación y de regresión logística entre las pruebas neuropsicológicas y genotipo. Resultado: El polimorfismo del DAT1 no mostró asociación con TDAH, ni con alteraciones en las funciones ejecutivas. El genotipo 10/10 del VNTR DAT1 se encontró asociado con el índice de velocidad de procesamiento (p <0,05). En el subgrupo hiperactividad hubo asociación con algunas subpruebas de flexibilidad cognitiva, número de respuestas correctas, total de errores, número de respuestas perseverativas (p ≤ 0.01). En el subgrupo mixto se asoció con índice de comprensión verbal (p <0,05). Conclusiones: No hubo asociación entre el polimorfismo VNTR (DAT1) y el fenotipo de TDAH. Se encontraron asociaciones entre genotipo y algunos test de flexibilidad cognitiva e índice de comprensión verbal. Se establecieron los estadísticos genético poblacionales de este polimorfismo para la población analizada, el cual corresponde al primer reporte de una muestra de nuestro país.

Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and-202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency

Insulin-like growth factor type 1 (IGF1) is a mediator of growth hormone (GH) action, and therefore, IGF1 is a candidate gene for recombinant human GH (rhGH) pharmacogenetics. Lower serum IGF1 levels were found in adults homozygous for 19 cytosine-adenosine (CA) repeats in the IGF1 promoter. The aim of this study was to evaluate the influence of (CA)n IGF1 polymorphism, alone or in combination with GH receptor (GHR)-exon 3 and -202 A/C insulin-like growth factor binding protein-3 (IGFBP3) polymorphisms, on the growth response to rhGH therapy in GH-deficient (GHD) patients. Eighty-four severe GHD patients were genotyped for (CA) n IGF1, -202 A/C IGFBP3 and GHR-exon 3 polymorphisms. Multiple linear regressions were performed to estimate the effect of each genotype, after adjustment for other influential factors. We assessed the influence of genotypes on the first year growth velocity (1st y GV) (n = 84) and adult height standard deviation score (SDS) adjusted for target-height SDS (AH-TH SDS) after rhGH therapy (n = 37). Homozygosity for the IGF1 19CA repeat allele was negatively correlated with 1st y GV (P = 0.03) and AH-TH SDS (P = 0.002) in multiple linear regression analysis. In conjunction with clinical factors, IGF1 and IGFBP3 genotypes explain 29% of the 1st y GV variability, whereas IGF1 and GHR polymorphisms explain 59% of final height-target-height SDS variability. We conclude that homozygosity for IGF1 (CA) 19 allele is associated with less favorable short-and long-term growth outcomes after rhGH treatment in patients with severe GHD. Furthermore, this polymorphism exhibits a non-additive interaction with -202 A/C IGFBP3 genotype on the 1st y GV and with GHR-exon 3 genotype on adult height. The Pharmacogenomics Journal (2012) 12, 439-445; doi:10.1038/tpj.2011.13; published online 5 April 2011

Repeat-dose sirolimus pharmacokinetics and pharmacodynamics in patients with hepatic allografts

To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C(min,TN)) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients.

Genetically increased risk of sleep disruption in alzheimer's disease

STUDY OBJECTIVES: To investigate the role of a monoamine A oxidase promoter polymorphism in sleep disruption in Alzheimer's disease (AD). DESIGN: A case-control association analysis. SETTING: Sleep disturbance in AD is common, is extremely stressful for caregivers, and increases the risk of institutionalisation. It remains unclear why only some patients develop sleep disturbance; neuropathologic changes of AD are not typically seen in the areas of the brain responsible for sleep. We hypothesized that the risk of sleep disturbance is, at least in part, influenced by the availability of serotonin used for melatonin synthesis secondary to polymorphic variation at the enzyme monoamine oxidase A (MAO-A). PATIENTS: Patients with AD diagnosed according to standard criteria. INTERVENTIONS: Data were collected using the Sleep domain of the Neuropsychiatric Inventory with Caregiver Distress. Patients' cognition and function were assessed using the Mini-Mental State Examination and the Functional Assessment Staging. Genotyping of apolipoprotein E (APOE) and of the 30 bp variable number tandem repeat of the MAO-A promoter was by standard methods. MEASUREMENTS AND RESULTS: Of 426 patients surveyed, 54% experienced sleep disturbance. We found that the high-activity 4-repeat allele of the MAO-A VNTR promoter polymorphism confers increased susceptibility to sleep disturbance (p = .008). A quantitative sleep disturbance score was significantly higher in the patients possessing MAO-A 4-repeat allele genotypes. APOE had no influence on the development of an altered sleep phenotype. CONCLUSIONS: We conclude that sleep disturbance in AD is common and distressing and is associated with genetic variation at MAO-A.

Spatial attentional bias as a marker of genetic risk, symptom severity, and stimulant response in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable childhood onset disorder that is marked by variability at multiple levels including clinical presentation, cognitive profile, and response to stimulant medications. It has been suggested that this variability may reflect etiological differences, particularly, at the level of underlying genetics. This study examined whether an attentional phenotype-spatial attentional bias could serve as a marker of symptom severity, genetic risk, and stimulant response in ADHD. A total of 96 children and adolescents with ADHD were assessed on the Landmark Task, which is a sensitive measure of spatial attentional bias. All children were genotyped for polymorphisms (30 untranslated (UTR) and intron 8 variable number of tandem repeats (VNTRs)) of the dopamine transporter gene (DAT1). Spatial attentional bias correlated with ADHD symptom levels and varied according to DAT1 genotype. Children who were homozygous for the 10-repeat allele of the DAT1 30-UTR VNTR displayed a rightward attentional bias and had higher symptom levels compared to those with the low-risk genotype. A total of 26 of these children who were medication naive performed the Landmark Task at baseline and then again after 6 weeks of stimulant medication. Left-sided inattention (rightward bias) at baseline was associated with an enhanced response to stimulants at 6 weeks. Moreover, changes in spatial bias with stimulant medications, varied as a function of DAT1 genotype. This study suggests an attentional phenotype that relates to symptom severity and genetic risk for ADHD, and may have utility in predicting stimulant response in ADHD.

Risk of Alzheimer's disease is associated with a very low-density lipoprotein receptor genotype in Northern Ireland

The epsilon-4 allele of apolipoprotein E (APOE) is associated with increased risk of Alzheimer's disease (AD), but the pathogenic mechanism is unknown. The 5-repeat allele of a CGG repeat polymorphism in the 5' untranslated region of the very low-density lipoprotein receptor (VLDL-R) gene, a receptor for apoE, has been found to be associated with increased risk of AD in a Japanese population. Other groups have been unable to replicate this in American Caucasian populations. A case-control study utilizing a clinically well-defined group of late-onset AD patients (n = 108) and age- and sex-matched control subjects (n = 108) from Northern Ireland was performed to test this association in a relatively homogeneous population. The 9,9 genotype of the VLDL-R was found to be significantly increased in patients compared to controls (P = 0.003; Pcorr = 0.035), leading to an increased risk of AD to subjects with this genotype (OR = 3.9; 95% CI, 1.52-11.25). In contrast to results from the Japanese study, the 5-repeat allele was found to be significantly reduced in the patient group when compared to controls (P = 0.008; Pcorr = 0.047). The results from this study suggest that individuals who have the 9,9 genotype of the VLDL-R gene are at increased risk of AD in Northern Ireland.

Cell lines and animal model in the analysis of pharmacogenomics markers in childhood acute lymphoblastic leukemia

La leucémie aiguë lymphoblastique (LAL) est le cancer pédiatrique le plus fréquent. Elle est la cause principale de mortalité liée au cancer chez les enfants due à un groupe de patient ne répondant pas au traitement. Les patients peuvent aussi souffrir de plusieurs toxicités associées à un traitement intensif de chimiothérapie. Les études en pharmacogénétique de notre groupe ont montré une corrélation tant individuelle que combinée entre les variants génétiques particuliers d’enzymes dépendantes du folate, particulièrement la dihydrofolate réductase (DHFR) ainsi que la thymidylate synthase (TS), principales cibles du méthotrexate (MTX) et le risque élevé de rechute chez les patients atteints de la LAL. En outre, des variations dans le gène ATF5 impliqué dans la régulation de l’asparagine synthetase (ASNS) sont associées à un risque plus élevé de rechute ou à une toxicité ASNase dépendante chez les patients ayant reçu de l’asparaginase d’E.coli (ASNase). Le but principal de mon projet de thèse est de comprendre davantage d’un point de vue fonctionnel, le rôle de variations génétiques dans la réponse thérapeutique chez les patients atteints de la LAL, en se concentrant sur deux composants majeurs du traitement de la LAL soit le MTX ainsi que l’ASNase. Mon objectif spécifique était d’analyser une association trouvée dans des paramètres cliniques par le biais d’essais de prolifération cellulaire de lignées cellulaires lymphoblastoïdes (LCLs, n=93) et d’un modèle murin de xénogreffe de la LAL. Une variation génétique dans le polymorphisme TS (homozygosité de l’allèle de la répétition triple 3R) ainsi que l’haplotype *1b de DHFR (défini par une combinaison particulière d’allèle dérivé de six sites polymorphiques dans le promoteur majeur et mineur de DHFR) et de leurs effets sur la sensibilité au MTX ont été évalués par le biais d’essais de prolifération cellulaire. Des essais in vitro similaires sur la réponse à l’ASNase de E. Coli ont permis d’évaluer l’effet de la variation T1562C de la région 5’UTR de ATF5 ainsi que des haplotypes particuliers du gène ASNS (définis par deux variations génétiques et arbitrairement appelés haplotype *1). Le modèle murin de xénogreffe ont été utilisé pour évaluer l’effet du génotype 3R3R du gène TS. L’analyse de polymorphismes additionnels dans le gène ASNS a révélé une diversification de l’haplotype *1 en 5 sous-types définis par deux polymorphismes (rs10486009 et rs6971012,) et corrélé avec la sensibilité in vitro à l’ASNase et l’un d’eux (rs10486009) semble particulièrement important dans la réduction de la sensibilité in vitro à l’ASNase, pouvant expliquer une sensibilité réduite de l’haplotype *1 dans des paramètres cliniques. Aucune association entre ATF5 T1562C et des essais de prolifération cellulaire en réponse à ASNase de E.Coli n’a été détectée. Nous n’avons pas détecté une association liée au génotype lors d’analyse in vitro de sensibilité au MTX. Par contre, des résultats in vivo issus de modèle murin de xénogreffe ont montré une relation entre le génotype TS 3R/3R et la résistance de manière dose-dépendante au traitement par MTX. Les résultats obtenus ont permis de fournir une explication concernant un haut risque significatif de rechute rencontré chez les patients au génotype TS 3R/3R et suggèrent que ces patients pourraient recevoir une augmentation de leur dose de MTX. À travers ces expériences, nous avons aussi démontré que les modèles murins de xénogreffe peuvent servir comme outil préclinique afin d’explorer l’option d’un traitement individualisé. En conclusion, la connaissance acquise à travers mon projet de thèse a permis de confirmer et/ou d’identifier quelques variants dans la voix d’action du MTX et de l’ASNase qui pourraient faciliter la mise en place de stratégies d’individualisation de la dose, permettant la sélection d’un traitement optimum ou moduler la thérapie basé sur la génétique individuelle.