The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders

Comings, David E.

doi:10.1001/jama.266.13.1793

Cited by 261 publications

(172 citation statements)

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“…Thus, a model has been proposed in which frequent prefrontal activation during tic suppression may produce compensatory prefrontal cortex hypertrophy that aids in tic suppression [624,625], although it is not presently clear how such basal ganglia and prefrontal characteristics effects reward processing in TS. Variants in the DA receptor gene DRD 2 have also been associated with genetic risk for TS [626-628], but this finding is not consistent [629-633]. …”

Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

243

201

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This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

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Section: Reviewmentioning

confidence: 99%

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Dichter

Damiano

Allen

2012

J Neurodevelop Disord

243

201

View full text Add to dashboard Cite

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“…The greatest research has been on DRD4 with 7 repeats and the DAT1 40bp VNTR (Comings et al 1991, Cook et al 1995, Comings et al 1996, LaHoste et al 1996, Gill et al 1997, Swanson et al 1997, Castellanos et al 1998, Smalley et al 1998, Swanson et al 1998, Daly et al 1999, Farone et al 1999, Rowe et al 1999, Comings et al 2000, Eisenberg et al 2000, Kotler et al 2000, Muglia et al 2000, Tahir et al 2000 . Cook et al (1995) was among the first to find preferential transmission of the 40bp allele (allele 3) of a VNTR in the 3′ UTR of the DAT1 40bp VNTR gene (12p12.3), a finding replicated by others, but not all investigators (Gill et al 1997, Daly et al 1999).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

Barkley

Smith

Fischer

et al. 2006

American J of Med Genetics Pt B

103

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Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (N=122) and normal (N=67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7-repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a Card Playing Task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD.Children with Attention Deficit Hyperactivity Disorder (ADHD), or what was previously diagnosed as Hyperactive Child Syndrome, are characterized by developmentally inappropriate levels of inattentive, impulsive, and hyperactive behavior that arise early in childhood and occur across multiple settings (American Psychiatric Association, 1968, 1980, 2001. Follow-up studies of hyperactive children suggest that from 35-80 percent of NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cases diagnosed in childhood will persist into adolescence Gittelman et al., 1985). By adulthood, 49-66% will have significant symptoms of the disorder or meet diagnostic criteria for it (Barkley et al., 2002;Mannuzza et al., 1993Mannuzza et al., ,1998 Rasmussen & Gillberg, 2002;Weiss and Hechtman, 1993).Biological relatives of children with the disorder are more likely to have ADHD (Biederman et al. 1990, Biederman et al. 1992, Biederman et al. 1995, Maher et al. 1999, Samuel et al. 1999. Numerous twin studies found that genetic factors account for the majority of variance in this trait with an average heritability of .75-.80, with more recent studies u...

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“…1 The role of genetic factors in these dopaminergic pathways are of interest in identifying risk factors for addiction (e.g., [2][3][4] ). Many genes are involved in the regulation of the dopamine system, and the DRD2 gene is one of the most frequently studied in addictive disorders.…”

Section: Introductionmentioning

confidence: 99%

The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms

et al. 2006

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The dopamine receptor D2 (DRD2) gene has polymorphisms that have been linked to regulation of the dopamine system and to an increased prevalence of smoking. The present study examined the relationship of the DRD2 TaqI-A and -B polymorphisms with short-term clinical outcome (abstinence and withdrawal symptoms), collected from daily (14 pre-quit and 42 post-quit) diary data among smokers (n ¼ 116) treated with the nicotine patch plus either venlafaxine or placebo. The results showed that B1/B1 or B1/B2 smokers were slightly less likely to be abstinent on a given day than those homozygous for the TaqI-B2 allele. Significant DRD2 TaqI-B Â time interactions were found for several of the withdrawal scales, indicating that those smokers with the B1/B1 or B1/B2 genotypes tended to report more symptoms over time compared to those with the B2/B2 genotype. No interactions or main effects were found for the DRD2 TaqI-A polymorphism. The findings demonstrate that smokers homozygous for the TaqI-B2 allele experience progressive improvement in self-reported withdrawal symptoms while smokers with the TaqI-B1 allele showing little change.

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The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders

Abstract: --These results suggest the A1 allele of the DRD2 gene is associated with a number of behavior disorders in which it may act as a modifying gene rather than as the primary etiological agent.

Cited by 261 publications

References 0 publications

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms

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