I. Introduction. DSM-IV uses “phenomenological” rather than “etiological” subtypes of ADHD, but in DSM-V, an emphasis on etiology has been promised. Genetic and environmental etiologies have been proposed to account for the behavioral and neuropsychological characteristic of ADHD, but it is becoming increasingly clear that complex diseases such as ADHD result from the interplay of genetic and environmental risk factors.
II. Molecular Genetic Studies. The initial studies used the candidate gene approach based on the “dopamine hypothesis” of ADHD (Wender, 1971; Levy, 1991; Volkow, 1995). Two candidate genes were targeted— the dopamine transporter (DAT) gene (Cook et al., 1995) with a 40-bp VNTR in the 3’ untranslated (non-coding) region that defined the primary alleles by 9 or 10 repeats (9R or 10R), and the DRD4 gene, with a 48-bp VNTR in a coding region (exon 3) that defined the primary alleles 2, 4, or 7 repeats (2R, 4R, or 7R). In the initial studies of ADHD clinical samples, Cook et al (1995) reported that an increased prevalence (0.70 to 0.85) and transmission (0.50 to 0.60) of the most prevalent 10R-repeat DAT allele, and LaHoste et al (1996) observed a higher than expected frequency (0.28 versus 0.12) of the DRD4 7R allele. In general, subsequent studies replicated the initial findings of association of ADHD with the DRD4 gene but not with the DAT gene (see Li et al, 2006). The DRD4 7R allele shows signs of recent (50,000 years ago) positive selection, which may be related to migration and the “Out of Africa” expansion of the human population (see Wang et al, 2005). Ethnic variations exist in population prevalence of the DRD4 allele, with lower prevalence in some ethnic groups in Asia (see Leung et al, 2005) and higher in South America (see Hutz et al., 2000). However, in general findings are similar in ADHD groups from South America and North America (Rohde et al, 2005), but in some South American clinical samples there are indications of interaction of the DRD4 and DAT genes (Roman et al, 2001; Carrasco et al, 2006). Recently, Brookes et al (2006) assessed 51 candidate genes in pathways related to dopamine, norepinephrine and serotonin, and confirmed association of ADHD with the DRD4 and DAT genes, and also provided suggestive evidence of association of ADHD with 16 other genes.
The functional significance of the DRD4 7R allele has been investigated by multiple groups (Swanson et al., 2000; Manor et al., 2002; Langley et al., 2003; Bellgrove et al., 2005), using neuropsychological tasks that required speeded response and comparing subgroups based on the 7-present and 7-absent genotype (i.e., those with and without a 7R allele) on measures of reaction time (RT) and RT variability. In general, the 7-present subgroups had faster and less variable responses on choice RT tasks than the 7-absent subgroups. Based on performance on the Matching Familiar Figures test, Langley et al. (2003) suggested ADHD children with the 7-present genotype had an impulsive style of responding, and Kieling et al. (2006) provided similar evidence of impulsive responding on the Continuous Performance Test. These studies provided support for the speculation by Swanson et al (2000 and 2007) that the presence of the 7R allele identifies a genetic variant of ADHD characterized by a cognitive style that produces behavioral excesses without the usual cognitive deficits (slow and variable RT), while the absence of the 7R allele identifies an environmental variant of ADHD characterized by both behavioral excesses and cognitive deficits on speeded tasks (slow and variable RTs).
Genome scans (see Fisher et al., 2002 and Bakker et al., 2003) have also been used in attempts to discover additional genes involved in the etiology of ADHD. Neither of these genome scans revealed a strong signal from a specific location on the human genome to direct the search for a specific gene, and the reported weak signals were different for these two genome scans (Fisher et al: 5p, 10q, 12q, and 16p; Bakker et al: 15q, 7p, and 9q). Ogdie et al (2003) provided a report on an expansion of the sample reported by Fisher et al (2002), and reported a signal for a gene in a region on 17p11 previously linked to autism. Arcos-Burgos et al. (2005) conducted a family study of a population isolate and identified linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11.
The lack of a strong signal from genome scans does not discount the existence of genes with high probability risk alleles, of multiple genes that combine to confer risk for ADHD, or of genes with effects that depend on interactions with environmental factors.
III. Environmental Studies. Taylor and Rogers (2005) review this area in detail. Linnett et al (2003) reviewed the literature on maternal lifestyle factors that exposed the developing fetus to nicotine, alcohol, caffeine, and stress, and only nicotine conferred risk for ADHD (see Millberger et al, 1996 and Thapar et al., 2003). Schmidt et al (2006) extended this finding and showed smoking during pregnancy was associated with ADHD-Inattentive Type. In a population sample, Braun et al (2006) reported 31.7% were exposed to prenatal tobacco exposure, which was associated with ADHD diagnosis (odds ratio = 2.5, with a population attributable fraction = 18.4%). Braun et al. (2006) also showed that exposure to very low levels of lead (in the range of 1-2 ug/dL) was common (7.9%) and was associated with ADHD (odds ratio = 4.1, with a population attributable fraction = 21.1%).
Barker et al (1989) proposed the hypothesis of developmental origins of health and disease (DOHaD), which was been elaborated by Gluckman and Hanson (2004). A similar hypothesis was proposed by Lou (1996), who revised the notion that a variety of types and degrees of stress during pregnancy produced specific minimal brain damage (Bax and McKeith, 1962) to striatal dopamine neurons and as a consequence, behavioral excesses and attentional deficits manifested as symptoms of ADHD. Recently, in a PET study of adolescents born premature, Neto et al (2002) documented low levels of extracellular dopamine in striatal regions, consistent with the prediction of Lou (1996). In separate studies, similar abnormal (blunted) catecholamine response to stress was documented in children with a history of traumatic brain injury (Konrad et al, 2003) and ADHD (Wigal et al., 2003). Swanson et al (2007) review these and other studies and suggested that the etiology of an environmental variant of ADHD (associated with the 7-absent genotype) was related to subtle damage to striatal dopamine neurons during fetal development, while the etiology of a genetic variant (associated with the 7-present genotype) was related to the inheritance of a subsensitive dopamine receptor.
IV. Gene-Environment Interaction. Few molecular genetic studies of ADHD have addressed gene-environment interactions. Kahn et al (2003) evaluated maternal smoking and the DAT gene and found for cases with maternal smoking during pregnancy, ADHD symptoms were more severe in individuals homozygous for the most frequent allele of the DAT gene (the 10R/10R genotype) but not if other alleles were present (e.g., the 9R/10 or the 9R/9R genotype). Brookes et al (2006) evaluated the DAT gene and two environmental factors, maternal alcohol consumptions (any vs. none) and heavy smoking (at least 20 cigarettes/day), during pregnancy. They reported linkage disequilibrium (non-random association of alleles) was present only those cases where maternal alcohol consumption was reported, and that the interaction of DAT genotype with maternal smoking during pregnancy was not significant.
V. Conclusions and Next Steps. Much larger sample sizes will be required to go beyond these important first steps to evaluate gene by environment interactions related to ADHD. The National Children’s Study (NCS) (see www.nationalchildrensstudy.gov) planned for the USA will recruit a large birth cohort of 100,000 children and to obtain broad measures of exposure and outcome taken in 16 visits scheduled across stages of development. As outlined in Landrigan et al. (2006), the NCS assessments will occur before conception; 3 times during pregnancy; at birth; at 1, 6, 12, and 18 months of age in early childhood; at 3, 5, 7, 9, and 12 years of age in childhood; at 16 and 20 years of age in adolescence. This should provide a large sample of affected children (3,000 to 5,000 with diagnoses of ADHD, depending on diagnostic criteria) with careful documentation of genetic and environmental exposures that will allow for evaluation of critical issues about the genetic and environmental contributions to ADHD as well as other childhood disorders.
Swanson et al (2007) suggested the evaluation of subtypes of ADHD would be to consider two types of etiologic factors – genetic and environmental. The review presented here suggests the genetic factors should include at a minimum the DRD4 and DAT genotypes, and the environmental factors should include at a minimum some environmental toxicants (nicotine, alcohol, and lead) and some pregnancy factors (preterm birth and small size due to growth restriction).
James M. Swanson, Ph.D. Professor of Pediatrics; Director, Child Developmental Center, University of California, Irvine, USA.
Dr. Armando Filomeno thanks the distinguished psychologist and neuroscientist for this article which he translated into Spanish for APDA’s electronic newsletter nº 15, issued on March 25, 2007.
Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG, Rapoport JL, Berg K, Bailey-Wilson JE, Muenke M. (2004). Attention-Deficit/Hyperactivity Disorder in a Population Isolate: Linkage to Loci at 4q13.2, 5q33.3, 11g22, and 17p11. Am J Hum Genetics. 75: 998-1014.
Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ et al. (2003). A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet. 72:1251-1260.
Barker DJO, Osmond C, Winter PD, Margetts B and Simmonds SJ. (1989). Weight in infancy and death from ischaemic heart disease. Lancet. 2:577-580.
Bax M and McKeith RM, eds. Minimal Cerebral Dysfunctions. Clinics in Developmental Medicine. Lavenham, Suffolk: The Lavenham Press LTD, 1962.
Bellgrove MA, Hawi Z, Lowe N, Kirley A, Robertson IH and H Gill. (2005). DRD4 gene variants and sustained attention in ADHD: effects of associated alleles at the VNTR and -521 SNP. Am J Med Genet B Neuropsychiatr Genet. 136:81-6.
Braun J, Kahn RS, Froehlich T, Aulnger P and BP Lanphear. (2006). Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in US Children. Environmental Health Perspectives. 114:1904-9.
Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N, Aneey R, Franke B, Gill M, Ebstein R, Buitelaar J, Sham P, Campbell D, Knight J, Andreou P, Altink A, Amold R, Boer F, Buschgens et al. (2006). The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry. 11: 934-953.
Brookes KJ, Mill J, Guindalini C, Curran S, Xu, X, Knight J, Chen CK, Huang YS, Sethna V, Taylor E, Chen W, Breen G, Asherson P. (2006). A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry. 63: 74-81.
Carrasco X, Rothhammer P, Moraga M, Henriquez H, Chakraborty R, Aboitiz F, Rothhammer F. (2006). Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for ADHD in Chilean families.Am J Med Genet B Neuropsychiatr Genet. 141:51-4 .
Cook EH, Jr., Stein MA, Krasowski MD, Cox, NJ, Olkon DM, Kieffer JE, et al. (1995). Association of attention deficit disorder and the dopamine transporter gene. Am J Hum Genet. 56:993-998.
Crowe RR. (1993). Candidate genes in psychiatry: an epidemiological perspective. Am J Med Genet. 48:74-77.
Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al.(2002). A genome wide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet. 70:1183-1196.
Gillman M. (2005). Developmental Origins of Health and Disease. New England Journal of Medicine. 353:1848-50.
Gluckman PD and MA Hanson. (2004). Living with the Past: Evolution, Development, and Patterns of Disease. Science. 305: 1733-6.
Hutz MH, Almeida S, Coimbra CE Jr, Santos RV, Salzano FM. (2000). Haplotype and allele frequencies for three genes of the dopaminergic system in South American Indians. Am J Hum Biol. 12:638-645.
Kahn RS, Khoury J, Nichols WC, Lanphear BP. (2003). Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatrics. 143: 104_110.
Kieling C, Roman T, Doyle AE, Hutz MH, Rohde LA. (2006). Association between DRD4 gene and performance of children with ADHD in a test of sustained attention. Biol Psychiatry. 10:1163-5.
Knopik VS, Health AC, Jacob T, Slutske WS, Bucholz KK, Madden PAF, Walron M, Martin NG. (2006). Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychological Medicine. 36: 1461-1471.
Konrad K, Gauggel S, Schurek J. (2003). Catecholamine functioning in children with traumatic brain injuries and children with attention-deficit/hyperactivity disorder. Brain Res Cogn Brain Res. 16:425-33.
LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL. (1996). Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Molecular Psychiatry. 1:121-124.
Landrigan PJ, Trasande L, Thorpe LE, Gwynn C, Lioy PJ, D’Alton ME, Lipkind HS, Swanson J, Wadhwa PD, Clark EB, Rauh VA, Perera FP, Susser E. (2006). The National Children’s Study: a 21-year prospective study of 100,000 American children. Pediatrics 118:2173-86.
Langley K, Marshall L, van den Bree M, Thomas H, Owen M, O’Donovan M et al. (2004). Association of the dopamine D4 receptor gene 7-repeat allele with neuropsychological test performance of children with ADHD. Am J Psych 161:133-138.
Leung PWL, Lee CC, Hung SF, Ho TP, Tang CP, Kwong SL, Leung SY, Yuen ST, Lieh-Mak F, Oosterlaan J, Grady D, Harxhi A, Ding YC, Chi HC, Flodman P, Shuck S, Spence MA, Moyzis R, Swanson JM. (2005). Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention deficit/hyperactivity disorder (ADHD): Increased prevalence of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 133(1):54-6.
Levy F. (1991). The dopamine theory of attention deficit hyperactivity disorder (ADHD). Australian and New Zealand Journal of Psychiatry. 25:277-283.
Li D, Sham PC, Owen MJ, He L. (2006). Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet. 15: 2276-84.
Linett K, Dalsgaard S, Obel C, Wisbord K, Henriksen TB, Rodriguez A, Kotimaa A, Moilanen I, Thomsen PH, Olsen J, Jarvelin M. (2005). Maternal Lifestyle Factors in Pregnancy Risk of Attention Deficit Hyperactivity Disorder and Associated Behaviors: Review of the Current Evidence. Am J Psychiatry. 160:1026-1040.
Linett KM, Wisborg K, Agerbo E, Sechor NJ, Thomsen PH, Henriksen TB. (2006). Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child. 91:655-60.
Lou HC. (1996). Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxis-haemodynamic encephalophy. Acta Paediatr. 85: 1266-1271.
Manor I, Tyano S, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP. (2002). The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in a family-based design and impair performance on a continuous performance test (TOVA). Mol Psychiatry. 7:790-794.
Millberger S, Biederman J, Faraone SV, Chen L, Jones L. (1996). Is maternal smoking during pregnancy a risk factor for attention deficit hyperactivity disorder in children? Am J Psychiatry. 153: 1138-1142.
Mick E, Biederman J, Faraone SV, Sayer J, Kleinman S. (2002). Case-Control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug-use during pregnancy. J Am Acad Child Adolesc Psychiatry. 41:378-85.
Neto P, Lou H, Cumming P, Pryds O, Gjedde A. (2002). Methylphenidate-evoked potentiation of extracellular dopamine in the brain of adolescents with premature birth. Ann N Y Acad Sci. 965:434-439.
Ogdie M, Macphie IL, Minassian SL, Yang M, Fisher SE, Francis CF, Cantor RM, MacCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL. (2003). A genome wide scan for attention-deficit/hyperactivity disorder: suggestive linkage on 17p11. Am J Hum Genet. 72:1268-1279.
Rohde LA, Szobot C, Polanczyk G, Schmitz M, Martins S, Tramontina S. (2005). Attention-deficit/hyperactivity disorder in a diverse culture: do research and clinical findings support the notion of a cultural construct for the disorder? Biol Psychiatry 57:1436-41.
Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz MH. (2001). Attention-deficit hyperactivity disorder: a study of association with both the dopamine transporter gene and the dopamine D4 receptor gene. Am J Med Genet. 105:471-8.
Schmitz M, Denardin D, Laufer Silva T, Pianca T, Hutz MH, Faraone S, Rohde LA. (2006). Smoking during pregnancy and attention-deficit/hyperactivity disorder, predominantly inattentive type: a case-control study. J Am Acad Child Adolesc Psychiatry. 11:1338-45.
Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S. (1998). Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Molecular Psychiatry, 3(1):38-41.
Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos G, Volkow N, Taylor E, Casey BJ, Castellanos FX, and Wadhwa. (2007). Etiologic Subtypes of ADHD: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis. Neuropsychology Review 17: 39-59.
Taylor E and Rogers JW. (2005). Practitioner review: early adversity and developmental disorders. J Child Psychology and Psychiatry. 46: 451-467.
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS et al. Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. (1995). Arch Gen Psychiatry; 52:456-463.
Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK. (2004). The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 74(5):931-944.
Wender P. (1971). Minimal brain dysfunction in children. New York: Wiley-Liss.
Wigal SB, Nemet D, Swanson JM, Regino R, Trampush J, Ziegler MG, Cooper DM. (2003). Catecholamine response to exercise in children with attention deficit hyperactivity disorder. Pediatr Res, 53(5):756-761.