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Am J Hum Genet. 1998 December; 63(6): 1767–1776. | PMCID: PMC1377649 |
Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. I D Waldman, D C Rowe, A Abramowitz, S T Kozel, J H Mohr, S L Sherman, H H Cleveland, M L Sanders, J M Gard, and C Stever Department of Psychology, Emory University, Atlanta, Georgia, USA. waldman@ss.emory.edu Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children. The Full Text of this article is available as a PDF (259K). These references are in PubMed. This may not be the complete list of references from this article. - Amara SG, Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci. 1993;16:73–93. [PubMed]
- Barr CL, Kidd KK. Population frequencies of the A1 allele at the dopamine D2 receptor locus. Biol Psychiatry. 1993 Aug 15;34(4):204–209. [PubMed]
- Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH. Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking. Nat Genet. 1996 Jan;12(1):81–84. [PubMed]
- Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT. Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder. J Am Acad Child Adolesc Psychiatry. 1990 Jul;29(4):526–533. [PubMed]
- Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry. 1991 May;148(5):564–577. [PubMed]
- Cook EH, Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL. Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet. 1995 Apr;56(4):993–998. [PubMed]
- Curtis D, Sham PC. A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet. 1995 Mar;56(3):811–812. [PubMed]
- Doucette-Stamm LA, Blakely DJ, Tian J, Mockus S, Mao JI. Population genetic study of the human dopamine transporter gene (DAT1). Genet Epidemiol. 1995;12(3):303–308. [PubMed]
- Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet. 1996 Jan;12(1):78–80. [PubMed]
- Ewens WJ, Spielman RS. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995 Aug;57(2):455–464. [PubMed]
- Gill M, Daly G, Heron S, Hawi Z, Fitzgerald M. Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry. 1997 Jul;2(4):311–313. [PubMed]
- Gillis JJ, Gilger JW, Pennington BF, DeFries JC. Attention deficit disorder in reading-disabled twins: evidence for a genetic etiology. J Abnorm Child Psychol. 1992 Jun;20(3):303–315. [PubMed]
- Giros B, Jaber M, Jones SR, Wightman RM, Caron MG. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996 Feb 15;379(6566):606–612. [PubMed]
- LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996 May;1(2):121–124. [PubMed]
- Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. [PubMed]
- Loeber R, Dishion T. Early predictors of male delinquency: a review. Psychol Bull. 1983 Jul;94(1):68–99. [PubMed]
- Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M. Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993 Jul;50(7):565–576. [PubMed]
- Morrison JR, Stewart MA. The psychiatric status of the legal families of adopted hyperactive children. Arch Gen Psychiatry. 1973 Jun;28(6):888–891. [PubMed]
- Neiswanger K, Kaplan BB, Hill SY. What can the DRD2/alcoholism story teach us about association studies in psychiatric genetics? Am J Med Genet. 1995 Aug 14;60(4):272–275. [PubMed]
- Nöthen MM, Propping P, Fimmers R. Association versus linkage studies in psychosis genetics. J Med Genet. 1993 Aug;30(8):634–637. [PubMed]
- Plomin R, Owen MJ, McGuffin P. The genetic basis of complex human behaviors. Science. 1994 Jun 17;264(5166):1733–1739. [PubMed]
- Rowe DC, Stever C, Gard JM, Cleveland HH, Sanders ML, Abramowitz A, Kozol ST, Mohr JH, Sherman SL, Waldman ID. The relation of the dopamine transporter gene (DAT1) to symptoms of internalizing disorders in children. Behav Genet. 1998 May;28(3):215–225. [PubMed]
- Schaid DJ, Sommer SS. Comparison of statistics for candidate-gene association studies using cases and parents. Am J Hum Genet. 1994 Aug;55(2):402–409. [PubMed]
- Silberg J, Rutter M, Meyer J, Maes H, Hewitt J, Simonoff E, Pickles A, Loeber R, Eaves L. Genetic and environmental influences on the covariation between hyperactivity and conduct disturbance in juvenile twins. J Child Psychol Psychiatry. 1996 Oct;37(7):803–816. [PubMed]
- Spielman RS, Ewens WJ. The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet. 1996 Nov;59(5):983–989. [PubMed]
- Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PubMed]
- Thapar A, Hervas A, McGuffin P. Childhood hyperactivity scores are highly heritable and show sibling competition effects: twin study evidence. Behav Genet. 1995 Nov;25(6):537–544. [PubMed]
- Thomson G. Mapping disease genes: family-based association studies. Am J Hum Genet. 1995 Aug;57(2):487–498. [PubMed]
- Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics. 1992 Dec;14(4):1104–1106. [PubMed]
- Waldman ID, Robinson BF, Feigon SA. Linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder: extending the transmission disequilibrium test (TDT) to examine genetic heterogeneity. Genet Epidemiol. 1997;14(6):699–704. [PubMed]
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