Attention-Deficit Hyperactivity Disorder: A Category or a Continuum? Genetic Analysis of a Large-Scale Twin Study

Lévy, Florence; Hay, David; McStephen, Michael; Wood, Catherine; Waldman, Irwin D.

doi:10.1097/00004583-199706000-00009

Cited by 851 publications

(634 citation statements)

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“…Twin studies indicate that there are shared as well as independent genes contributing to the symptom dimensions of ADHD (Levy et al, 1997), thus we examine the genetic contribution to the dimensions separately. The marker rs2161961 showed significant association to both ADHD dimensions as rated by the parent (inattention: P = 0.003 and hyperactivity/impulsivity: P = 0.008) ( Table 3).…”

Section: Resultsmentioning

confidence: 99%

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

Laurin

Ickowicz

Pathare

et al. 2008

Journal of Psychiatric Research

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The dopamine system plays an important role in the regulation of attention and motor behavior, subsequently, several dopamine-related genes have been associated with Attention Deficit/ Hyperactivity Disorder (ADHD). Among them are the dopamine receptors D1 and D5 that mediate adenylyl cyclase activation through coupling with G s -like proteins. We thus hypothesized that the G s -like subunit Gα olf , expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. To evaluate the involvement of the Gα olf gene, GNAL, in ADHD, we examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families ascertained through a proband with ADHD (311 affected children) using the transmission/disequilibrium test (TDT). Categorical analysis of individual marker alleles demonstrated biased transmission of one polymorphism in GNAL intron 3 (rs2161961; P = 0.011). We also observed significant relationships between rs2161961 and dimensional symptoms of inattention and hyperactivity/ impulsivity (P = 0.003 and P = 0.008). In addition, because of recent evidence of imprinting at the GNAL locus, secondary analyses were split into maternal and paternal transmissions to assess a contribution of parental effects. We found evidence of strong maternal effect, with preferential transmission of maternal alleles for rs2161961A (P = 0.005) and rs8098539A (P = 0.035). These preliminary findings suggest a possible contribution of GNAL in the susceptibility to ADHD, with possible involvement of parent-of-origin effects.

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Section: Resultsmentioning

confidence: 99%

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

Laurin

Ickowicz

Pathare

et al. 2008

Journal of Psychiatric Research

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“…4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al 1990(Biederman et al , 1992Faraone et al, 1992Faraone et al, , 1994, twin (Thapar et al 1995;Silberg et al 1996;Levy et al 1997), and adoption studies (Alberts-Corush et al 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al 1996;Levy et al 1997).…”

mentioning

confidence: 86%

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

Kirley

Hawi

Daly

et al. 2002

Neuropsychopharmacology

107

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Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD).Attention Deficit Hyperactivity Disorder (ADHD) is a common condition of childhood affecting 3-6% of school age children worldwide (Barkley 1990), with males being affected three times more than females (Anderson et al. 1987; Baumgartel et al. 1995). Its core clinical features include excessive motor activity, impaired attention, and impulsivity. ADHD causes marked educational, social, and family difficulties for sufferers and their relatives. The condition is of early onset (usually before age 7) and tends to persist throughout childhood. Moreover, approximately 30-60% of children with ADHD have persisting psychopathology in adulthood (Gittelman et al. 1985;Weiss and Hechtman 1986; Barkley 1990;Swanson et al. 1998a). The exact etiology of ADHD is Received March 8, 2001; revised February 12, 2002; accepted February 20, 2002. Online publication: 2/28/02 at www.acnp.org/citations/ Npp022802254. 608 A. Kirley et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al. 1990(Biederman et al. , 1992Faraone et al., 1992Faraone et al., , 1994, twin (Thapar et al. 1995;Silberg et al. 1996;Levy et al. 1997), and adoption studies (Alberts-Corush et al. 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al. 1996;Levy et al. 1997). The exact mode of transmission remains unknown. Segregation analyses (Morrison and Steward 1974;Deutsch et al. 1990, Faraone et al. 1992, Hess et al. 1995 have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single gene inheritance is modest. The multifactorial concept is consistent with ADHD's high population prevalence (2-7%), high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.Dysregulation in catecholamine neurotransmission is implicated in the pathophysiology of ADHD (Faraone and Biederman 2002). The dopaminergic neurotransmitter system has been most extensively studied. This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al. 1996;Gainetdinov et al. 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al. 1999, Krause et al. 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.The gene encoding the dopamine transporter, DAT1, was the initial candidate gene studied. This gene is of particular interest, as the transporter is the principal target...

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“…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 using larger twin samples showing even higher heritability scores of 0.85 to 0.95 (Dick et al, 2004;Gjone et al 1996, Levy et al 1997, Rhee et al, 1999 Stevenson, 1992, Thapar et al 1999, Thapar et al 2000. Such findings initiated molecular genetic studies to identify gene polymorphisms linked to the disorder, particularly for dopamine regulators, given the pharmacological effects of stimulant medication, neuro-imaging studies implicating the prefrontal cortex and striatum, and animal studies using selective lesions of dopamine pathways.…”

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

104

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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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Attention-Deficit Hyperactivity Disorder: A Category or a Continuum? Genetic Analysis of a Large-Scale Twin Study

Cited by 851 publications

References 35 publications

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

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

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