Journal of Pediatric Psychology Advance Access published online on June 3, 2008
Journal of Pediatric Psychology, doi:10.1093/jpepsy/jsn049
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Genetics of Attention Deficit/Hyperactivity Disorder
1Texas Institute for Genomic Medicine, 2Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, and 3Shriners Hospitals for Children-Philadelphia
All correspondence concerning this article should be addressed to Deeann Wallis, PhD, Texas Institute for Genomic Medicine, 2121 W Holcombe Blvd., Houston, TX 77030, USA. E-mail: dwallis{at}tigm.org
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Abstract |
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 Top Abstract IntroductionComplexities in Defining the...Complexities in Studying...Finding the ADHD gene(s)ConclusionGlossaryReferences |
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Objective The intent of this review is to provide an overview for the practicing psychologist/psychiatrist regarding the complexities of and the most recent advances made in the study of the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Methods We review a variety of concepts including: (a) complexities involved in studying the genetics of ADHD, (b) evidence for a primarily genetic component of ADHD, (c) evidence suggesting that there are only a few genes with major effects contributing to ADHD, (d) identification of the best candidate genes, (e) linkage analysis for the identification of novel candidate genes, and (f) data on gene–environment interactions. Results It is now generally accepted that ADHD has a biological and even primarily genetic basis. However, despite the identification of several candidate genes, none of them seems to have a substantial effect and the exact etiology underlying ADHD has remained elusive. Genome-wide linkage analysis can help in the identification of novel candidate genes. While several independent groups have initiated these studies, we await further details and specific genes from fine-mapping studies. Most recently, researchers have been trying to identify gene by environment interactions to help understand ADHD. Replication of positive findings will be essential in teasing out these combinatorial influences. Conclusions Ideally, one day specific genes with major effects and specific risk factors with which they interact will be identified and we will be able to implement personalized medicine. Knowledge of such genes will allow us to identify specific diagnostic biological markers. In addition, defining the target genes is the first step in developing novel drug therapies to treat the ADHD symptoms that lead to impairment. Furthermore, such markers could also identify at risk individuals at a younger age in order to implement treatments sooner to decrease the severity of ADHD symptoms or even to prevent future ADHD symptomatology.
Key words: ADHD; association studies; DAT1; DRD4; genetics; linkage analysis.
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Introduction |
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TopAbstractIntroductionComplexities in Defining the...Complexities in Studying...Finding the ADHD gene(s)ConclusionGlossaryReferences |
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The main characteristic of attention-deficit/hyperactivity disorder (ADHD) is a persistent pattern of inattention and/or hyperactivity–impulsivity, which is more frequent and severe than is usually expected in individuals at a comparable level of development. The world-wide pooled prevalence of ADHD is estimated to affect
5.29% of school-aged children (Polanczyk, de Lima, Horta, Biederman, & Rohde, 2007
) and is therefore the most common childhood onset psychological disorder (Castellanos & Tannock, 2002; Pineda et al., 1999). Biological diagnostic markers do not exist. While behavioral modifications work well for some individuals, the most effective treatments specifically for symptoms of ADHD involve the use of stimulant medications (Abikoff et al., 2004; Horn et al., 1991; MTA Cooperative Group, 2004; Staller and Faraone, 2006). Hence, there is great interest in identifying the causes of ADHD so that individuals with ADHD can receive the most effective treatments. When thinking of genetic susceptibilities for ADHD (or any other behavior), the rationale is fairly straightforward (Fig. 1). We expect that a genetic variation in the DNA of a specific gene will lead to variation at the cellular level of the neuron. This variation may be in the differentiation, development, structure, or function of the neuron. Such a change will subsequently lead to variation at the level of the brain or "system" such that there are changes during system differentiation, development, structure, or function that lead to changes in behavior or phenotype. Genetic variants have already been shown to affect human behavior; examples include genes involved in Alzheimer's disease, Huntington's disease, and aggression due to changes in the gene for monoamine oxidase A (MAOA). While the underlying rationale is simplistic, the overall picture can be distorted by environmental risk factors, proper phenotypic assessment, and complex genetics (Fig. 1).
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While this review focuses on genetic causes of ADHD, it is important to remember that ADHD has other (nongenetic/environmental) etiologies as well. Disorders that impact brain development such as prenatal toxin exposure (e.g., lead, alcohol, and tobacco), prematurity, encephalitis, metabolic disorders, and certain genetic syndromes may lead to an increased risk of ADHD (Acosta, Arcos-Burgos, & Muenke, 2004
; Banerjee, Middleton & Faraone, 2007). In addition, brain injury or lesions to the prefrontal and parietal cortex increase risk for ADHD as these regions are most closely associated with inattention and inhibition. When unknown, such environmental phenocopies can confound genetic analysis. Further discussion of the role of environmental factors in ADHD is outside the scope of this review. However, as potential Gene by Environment (G x E) interactions also increase the risk for the disorder, we will briefly touch on some of the most recently identified interactions below after we have discussed some of the specific candidate genes for ADHD. |
Complexities in Defining the ADHD Phenotype |
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Phenotype definition has particular and direct implications on gene finding strategies. As such, we review some of the myriad problems in defining the ADHD phenotype.
Definition and Diagnosis of ADHD
First, the basic concept of ADHD has changed over time and is even currently defined differently in various parts of the world. Over time it has been called hyperkinetic disorder, attention-deficit disorder, and now attention-deficit/hyperactivity disorder. At this time, it is described somewhat differently in the Diagnostic and Statistical Manual of Mental Disorders-IV and in the International Statistical Classification of Diseases and Related Health Problems 10. Looking into the future, some experts are discussing whether or not factors such as age and gender should result in separate and possibly more appropriate diagnostic criteria. In addition, the diagnosis is made differently across clinicians and disciplines making studies hard to compare. Diagnosis can vary from one nonstructured interview with one caregiver all the way to a battery including a semi-structured interview and rating forms with the caregiver(s); rating forms with the teacher(s) or co-worker(s); and brain imaging, an interview, rating forms, and a psychoeducational screen with the identified patient. Consistent methods to define ADHD across disciplines and cultures would be useful to epidemiologists and geneticists alike.
ADHD Subtypes and Latent Classes
It is important to understand that ADHD is the extreme end of a continuum of self-control as opposed to an isolated disorder. Hence, its diagnosis may reflect an arbitrary cutoff of what is considered normal. Although the majority of people with ADHD have symptoms of both hyperactivity–impulsivity and inattention, there are some individuals in whom one or the other pattern is predominant. This has resulted in the subtyping of ADHD into three groups. It is unclear whether these subtypes are causally different. Thus, geneticists are proposing even further subtyping. When considering a full behavioral spectrum that is represented on one end by hypoactivity and hyperattention and at the other end by hyperactivity and inattention, latent class cluster analysis defines 6–8 latent classes or groups (Rasmussen et al., 2002c; Rohde et al., 2001; Todd et al., 2001b). Presumably, correspondence between phenotypic variance and putative susceptibility genes might be improved (Todd et al., 2001a). This assumes that these subgroupings involve the same biological pathways as the disorder, but are less removed from gene action than is the diagnostic category. These new classifications are obtained directly from the response items, e.g., the DSM-IV symptoms, and group participants that share similar response patterns. These findings suggest the presence of more finely grained independent groups embedded within the ADHD phenotype than those acknowledged by current nosology (Rasmussen et al., 2002a,b). In addition, these latent classes exhibit comparable heritability and greater familiality than that of the DSM-IV subtypes (Neuman et al., 2001; Rasmussen et al., 2002a; Todd et al., 2001a). These findings further extend previous work and are most consistent with the presence of multiple independent forms of ADHD (Rasmussen et al., 2004). Accounting for such differences in genetic studies may be helpful to gene identification.
Comorbidities
Adding more difficulty to the assessment of ADHD is the fact that ADHD is often present with other diagnoses including externalizing disorders such as conduct disorder (CD) and oppositional defiant disorder (ODD), internalizing disorders such as Depression and Anxiety, Addictive Disorders, and Learning Disabilities (Biederman et al., 1992; for review see Biederman, 2004). Overall, perhaps, as many as 65% of children with ADHD will have one or more comorbid conditions (Dalsgaard, Mortensen, Frydenberg, & Thomsen, 2002; Willcutt, Hartung, Lahey, Loney, & Pelham, 1999; Willcutt & Pennington, 2000). Between 10% and 20% of children with ADHD have mood disorders, 20% have conduct disorders, (Biederman, Newcorn, & Sprich, 1991), and 30–45% have ODD. It has even been suggested that ADHD, ADHD + ODD, ADHD + CD be placed on a continuum of increasing levels of familial etiological factors and correspondingly severity of illness (Faraone, Biederman, Keenan, & Tsuang, 1991b). Thus, ADHD with and without certain comorbidities may be etiologically distinct. Using family study methodology, ADHD and antisocial disorders occurred in the same relatives more often than expected by chance alone suggesting that ADHD with and without antisocial disorders may be etiologically distinct (Faraone, Biederman, Jetton, & Tsuang, 1997). Additionally, ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD, ADHD and CD, ODD and CD, and CD and alcohol abuse/dependence (Jain et al., 2007). The fact that ADHD is comorbid with other disorders suggests that there is epistasis (involving an interaction among an unknown number of genes), genetic heterogeneity, and pleiotropy (where any gene may be associated with a range of phenotypes) (Castellanos & Tannock, 2002; Jain et al., 2007).
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Complexities in Studying Genetics of ADHD |
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ADHD as a complex trait
Due to the complexity seen in the inheritance of ADHD in families, it is considered by some to be a complex trait in that several different types of risk factors, both genetic and environmental, combine together (each having a small effect on increasing susceptibility to the disorder) through their additive and interactive effects. According to this point of view, if the cumulative susceptibility exceeds a threshold, then the individual will manifest ADHD. This view maintains that there is no one factor that is necessary or sufficient to cause ADHD and that these factors are interchangeable. This implies that multiple genes and or environmental risk factors work together to cause ADHD, and that ADHD does not seem to follow Mendelian segregation or assortment. However, we believe ADHD does follow Mendelian segregation and does have a large genetic component (as we discuss below), with only a few genes of major effect (also discussed below) in addition to many other smaller gene and/or environmental contributions. Thus, the quest to identify the genetic contributions continues.
There are several reasons why we might not be able to easily see the Mendelian segregation within a given family. First, there may be genetic heterogeneity (more than one gene causing susceptibility to ADHD). This makes it especially difficult to collect large multigenerational families to study ADHD as there is a high likelihood of bilineality (where both parents have ADHD and the gene(s) could come from both sides of the family as opposed to from just one parent) (see bilineality in Figure 2). In addition, different genes in different populations may lead to ADHD susceptibility. Alternatively, there may be allelic heterogeneity where different alleles at the same locus may confer risk or protection. Incomplete penetrance where a given gene variant does not always cause the phenotype may also play a role. In fact, it seems that many ADHD risk alleles are quite common variants in populations, and susceptibility might even be the rule rather than the exception (Arcos-Burgos & Acosta, 2007). Epistasis or pleiotropy may also play roles in ADHD (Jain et al., 2007). In light of the factors above, it is understandable how it may be challenging to discern the true Mendelian nature of the inheritance of ADHD within families.
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ADHD has a genetic component
To date, the causes of ADHD are unknown, but there is strong evidence and it is generally accepted that ADHD has a genetic component. This evidence comes from various types of genetic studies such as adoption, twin, and family studies, which have been conducted over the past 30 years. ADHD shows familiality (it runs in families) as well as heritability (it has a genetic component). In addition, this genetic contribution is seen regardless of whether ADHD is treated as a diagnostic category, a continuum of symptoms, or when using latent class analysis to define the phenotype.
Family studies have been conducted in order to assess the genetic influences involved in ADHD. This type of study is based on the premise that if ADHD has a genetic component, then the frequency of ADHD will be increased among the biological relatives of the initial affected individual (proband) when compared to the prevalence of ADHD in the general population (Lombroso, Pauls, & Leckman, 1994). A major critique of this type of study is that it is unable to tease out environmental effects from genetic effects. Thus, the common diagnosis among family members is just as likely to be due to environmental factors, such as socio-economic status or cultural influences. However, if it can be shown that the transmission pattern is consistent with a particular Mendelian mode of inheritance (i.e., autosomal dominant), it is unlikely that the ADHD could have been completely caused by the environment. Figure 2 illustrates a pedigree that segregates ADHD (and other comorbidities) in a pattern that is consistent with a Mendelian dominant mode of inheritance. Furthermore, ADHD was diagnosed five times more frequently in relatives of probands with ADHD than in relatives of control patients (Biederman et al., 1986). This significantly increased risk cannot be fully accounted for by gender, generation of relative, the age of the proband, social class, or the intactness of the family (Biederman et al., 1992; Biederman, Faraone, Keenan, Knee, & Tsuang, 1990). An exploratory study of ADHD among second degree relatives of children with ADHD established that the risk of ADHD was greatest when the second degree relative was biologically related to an affected parent of an affected child (Biederman et al., 1994). These results support the notion that genetic influences play an important part in the etiology of ADHD (Faraone, Biederman, Keenan, & Tsuang, 1991a).
Twin studies serve as a powerful method for researchers to assess the contribution of genetic factors in the etiology of ADHD. This approach was designed in order to address the debate over whether genetic or environmental factors are the determinants in behavioral disorders. The theoretical basis for twin studies is rather simple. Monozygotic (MZ) twins share 100% of their genes, while dizygotic (DZ) twins are like siblings as they share close to 50%. With this in mind, the relative importance of genetic factors can be assessed by comparing the degree to which MZ and DZ twins and their siblings have similar phenotypes or diagnoses. Hypothetically, MZ twins should have a concordance rate of 1, while the DZ twins should have a 0.5 concordance rate for a fully penetrant autosomal dominant gene and a 0.25 concordance rate for an autosomal recessive gene. However, this rarely happens due to environmental effects and complex genetic inheritance, thus the concordance rates will approach those percentages (or a greater MZ than DZ concordance rate) if there is a significant genetic factor which is contributing to the occurrence of ADHD (Lombroso, Pauls, & Leckman, 1994). Many twin studies have been performed in several countries (Australia, Sweden, UK, and US) and the average concordance rate is 0.76, indicating that genetics contributes 70–80% to ADHD and environment contributes 20–30% (Biederman and Faraone, 2005).
In an attempt to address the problem of environmental factors, adoption studies were developed. These look more closely at the role played by environmental factors. Adoption studies are based on the premise that when a diagnosis has a genetic basis, the frequency of that diagnosis among the members of the biological family will be higher than the frequency of the diagnosis among the adoptive family members. Conversely, when environmental factors are more dominant in the etiology of the diagnosis than genetic factors, the frequency of the diagnosis will be increased among the adoptive family members when compared to the biological family members (Lombroso, Pauls, & Leckman, 1994). One study found that 6% of the adoptive parents of probands with ADHD had ADHD compared with 18% of the biological parents of probands with ADHD and 3% of the biological parents of the control probands, again indicating that ADHD has a genetic component (Sprich, Biederman, Crawford, Mundy, & Faraone, 2000).
ADHD segregation in families
When looking at families with ADHD, it is difficult to determine the mode of genetic inheritance. Hence, several independent segregation analyses have been performed on pedigrees segregating ADHD in order to determine the likelihood of involvement of major genes (Mendelian inheritance), environment, and cohort (randomness) effects acting alone or as part of mixed models. The first study involved 257 nuclear families and found that the best fitting model was that of a major codominant gene (Faraone et al., 1992). Another study involved 495 families, where a subgroup of 130 families was utilized and supported a sex-dependant Mendelian codominant model (Maher, Marazita, Moss, & Vanyukov, 1999). A third segregation analysis of 53 families from a genetic isolate has failed to reject a Mendelian dominant and codominant major gene model of inheritance, while rejecting multifactorial, nongenetic familial transmission, and various mixed models (Arcos-Burgos et al., 2002; Lopera et al., 1999; Maher, Marazita, Moss, & Vanyukov, 1999). Although these three studies were performed in different populations, with various methods to test inheritance, they converge in explaining the predisposition to ADHD as a consequence of a Mendelian factor. This major gene has an estimated penetrance of about 50% and differential sex liability. These studies suggest that there are only a few genes that are the major cause of ADHD. Note that this is in contrast to the theoretical threshold model suggesting that there are many genes with small effects.
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Finding the ADHD gene(s) |
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Thus, if we believe that ADHD has a genetic basis and that perhaps only a few genes are the major cause of ADHD, how can we identify them? In essence, there are two general ways to look specifically for genes involved in ADHD. One way involves assimilating what we know about ADHD, its phenotype and its pathophysiology and picking candidate genes that we know play a role in these processes. Variants within these candidate genes are then tested for association with the ADHD phenotype. A second method involves testing families and tracking genomic variations (called polymorphisms) or markers with the ADHD phenotype to look for association or linkage. Once a linked region has been established, known genes in the area can be identified and assessed. Either way, patient DNA must be collected, but different types of cohorts may be assembled. The recommended strategies for mapping genes that convey the susceptibility to ADHD have consisted of collecting large samples of: affected sibling pairs, family based parent-proband trios, cases and controls, and large multigenerational families from population isolates (Faraone, 2002
; Faraone, Biederman, & Monuteaux, 2000; Palacio et al., 2004). Finding families to study ADHD has been difficult due to: the ADHD phenotype itself with childhood onset, variable expression ranging from inattentive to hyperactive, sex-dependant phenotype variability, phenotype transformation over time, phenocopies, presence of comorbidity, and assortative mating.
The Most Promising Candidate Genes
Many candidate gene studies have used association methods to see if gene variants affect the susceptibility of ADHD by comparing the variants in cases and controls or by family-based studies showing greater transmission of one variant from affected parents to ADHD offspring. The Transmission Disequilibrium Test (TDT) tests whether preferential transmission of a particular allele occurs between affected parent and affected offspring. If so, this suggests that the variant may be involved in disease susceptibility.
The analysis of candidate genes has generally focused on genes in the dopamine and serotonin molecular pathways. It is believed that these neurotransmitters play some role in ADHD. Various lines of study converge in implicating altered dopamine and/or serotonin metabolism in the brain. The first line of evidence involves the successful treatment with stimulant medications that facilitate the release of neurotransmitters, such as dopamine and block dopamine reuptake in the synapse by blocking the dopamine transporter protein. A second line of evidence comes from neuroimaging studies, which implicate changes in brain regions rich in dopaminergic innervations in individuals with ADHD (Castellanos et al., 1996). The final line of evidence comes from studies of animal models of ADHD with altered dopamine metabolism. The serotonergic system is also implicated in ADHD as reduced central serotonergic activity is implicated in poor impulse regulation in animals, adults, and children. Interestingly, low platelet and whole blood serotonin levels have been reported in ADHD probands (Bhagavan, Coleman, & Coursin, 1975). The action of serotonin is terminated by reuptake via the sodium-dependant serotonin transporter 5-HTT.
There have been over 215 reports of association of various candidate genes and ADHD. The candidate genes and their ADHD association studies have been recently and extensively reviewed (Bobb, Castellanos, Addington, & Rapoport, 2004). Only 36% of the studies were positive, while 17% show trends and 47% were negative (Bobb, Castellanos, Addington, & Rapoport, 2004). Hence, the literature contains more nonreplications than positive findings of association, suggesting that multiple replications are necessary before a true association is made between a given marker or candidate and ADHD. Also, none of the reported candidates appear to have substantial effects. It is important to note that virtually none of the studies assessing association and a given candidate gene meet sample size recommendations for achieving adequate power to find association with genes of modest effects (Risch & Merikangas, 1996). Thus, more individuals with ADHD and their families need to be recruited for these studies. Another limitation is population stratification, or the fact that different populations have different allele frequencies at a given genetic locus.
Some of the candidate genes where positive associations have been replicated include the dopamine transporter gene (DAT1or SLC6A3), the dopamine D2, D4, and D5 receptor genes, the serotonin transporter gene (SLC6A4 or 5-HTT), the serotonin 2A receptor gene (5-HT2A), and SNAP25. Other genes that have received significant study include the norepinephrine transporter (NET), catechol-O-methyltransferase (COMT), and the nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4). (For a more thorough listing of the various ADHD candidate genes see Bobb, Castellanos, Addington, & Rapoport, 2004).
DAT1
The dopamine transporter gene, DAT1, mediates the active reuptake of dopamine from the synapse and is a principal regulator of dopaminergic neurotransmission. Interestingly, many individuals with ADHD respond well to medications such as methylphenidate that block DAT1 leading to increased amount and duration of dopamine in the synapse (Amara & Kuhar, 1993). In addition, the increased density of the dopamine transporter in ADHD brains is reported to normalize with methylphenidate treatment (Krause, Dresel, Krause, Kung, & Tatsch, 2000). Furthermore, mice that lack the dopamine transporter gene are hyperactive (Giros, Jaber, Jones, Wightman, & Caron, 1996). Multiple studies have looked at DAT1 polymorphisms and their association with ADHD, and some replicate positive associations (Brookes et al., 2006a,b; Cook et al., 1995; Das & Mukhopadhyay, 2007; Feng et al., 2005b; Friedel et al., 2007; Genro et al., 2007; Gill, Daly, Heron, Hawi, & Fitzgerald, 1997; Ouellet-Morin et al., 2007; Simsek, Al-Sharbati, Al-Adawi, Ganguly, & Lawatia, 2005; Waldman et al., 1998). In fact, DAT1 was believed to represent one of the first replicated relations of a candidate gene and a psychiatric disorder in children.
DRD4
The dopamine D4 receptor gene, DRD4, is the most replicated gene in the field with over 20 studies examining an association between DRD4 and ADHD (Faraone, Doyle, Mick, & Biederman, 2001). DRD4 encodes a 7-transmembrane G-protein-coupled dopamine receptor and is expressed in regions implicated in ADHD, such as the limbic system, frontal cortex, and globus pallidus. DRD4 mediates postsynaptic actions of dopamine. Several studies have replicated linkage or association between ADHD and polymorphisms within DRD4 (Arcos-Burgos et al., 2004a; Benjamin et al., 1996; Ebstein et al., 1996; LaHoste et al., 1996; Swanson et al., 2000a,b). One DRD4 polymorphism may have functional implications. This polymorphism involves a short and a long form of DRD4 with the two of them having differential binding to clozapine and spiperone (Van Tol et al., 1992). Mice deficient for DRD4 exhibit reductions in behavioral responses to novelty, reflecting a decrease in novelty-related exploration (Dulawa, Grandy, Low, Paulus, & Geyer, 1999). Novelty seeking may be associated with impulsiveness and excitability—both symptoms of ADHD.
5-HTT
When the neurotransmitter serotonin is released into the synapse, it is cleared from synaptic spaces by the serotonin transporter gene (SLC6A4 or 5-HTT). 5-HTT has a polymorphism leading to short and long variants where the short variant results in reduced transcription and lower levels of protein. The long variant is associated with ADHD because serotonin is cleared more rapidly from the synapse resulting in reduced serotonin availability. Many studies indicate a positive association with 5-HTT and ADHD (Grevet et al., 2007; Heiser et al., 2007; Retz et al., 2002, 2004; Seeger, Schloss, & Schmidt, 2001; Zoroglu et al., 2002).
5-HT2A
The serotonin 2A receptor (5-HT2A) is also a good candidate gene because decreases in hyperlocomotion in mice given selective 5-HT2A agonists are observed (O’Neill, Heron-Maxwell, & Shaw, 1999). It may also decrease dopamine in the synapse when serotonergic agonists are injected into the striatum (Hawi et al., 2002). A few studies indicate positive associations with 5-HT2A polymorphisms and ADHD (Guimaraes et al., 2007; Quist et al., 2000).
SNAP25
Synaptosomal-associated protein, 25 kD, SNAP25, is expressed at the nerve terminal and is required for the fusion of synaptic vesicles loaded with neurotransmitters with the cell membrane so that exocytosis of the vesicle contents may occur. The coloboma mutant mouse model lacks SNAP25 and has motor hyperactivity. Several groups have demonstrated association of SNAP25 and ADHD (Barr et al., 2000, 2002; Brophy, Hawi, Kirley, Fitzgerald, & Gill, 2002; Feng et al., 2005a; Guan et al., 2008; Kim et al., 2007; Kustanovich et al., 2003; Mill et al., 2002, 2004, 2005).
COMT
COMT catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. Several studies have linked COMT variants with ADHD (Eisenberg et al., 1999; Qian et al., 2003), but it appears that there is not a strong association between COMT and ADHD (Cheuk and Wong, 2006).
NET1
The norepinephrine transporter (SLC6A2) is responsible for reuptake of norepinephrine into presynaptic nerve terminals and is a regulator of norepinephrine homeostasis. A few studies have found association with NET1 and ADHD (Bobb et al., 2005; Guan et al., 2008).
CHRNA4
The CHRNA4 is a member of a super family of ligand-gated ion channels with a high affinity for nicotine that upon stimulation promotes the release of dopamine. Several studies have found an association between ADHD and CHRNA4 (Comings et al., 2000; Guan et al., 2008; Kent et al., 2001; Todd, Lobos, Sun, & Neuman, 2003). Further, linkage analysis suggests the region around CHRNA4 may be linked to the ADHD phenotype (Arcos-Burgos et al., 2004b).
Linkage Studies
As the candidate gene approach has not been very productive in identifying ADHD genes with a major effect, a different strategy is needed to find the ADHD genes. Linkage studies are one possible way. Genetic linkage analysis is a statistical method that is used to associate markers with known locations on chromosomes with the disease phenotype. The main idea is that markers (and genes) that are located close together on the chromosome have a tendency to be passed on to the offspring together. Thus, if the disease is passed to offspring along with specific markers, then it can be concluded that the gene(s) that are responsible for the disease are located close to these markers. The advantage of this approach is that it does not assume where the genes might be found within the genome nor does it assume any biological role that the gene might play. This approach is referred to as positional cloning. Four groups have performed genome-wide linkage studies to date. One group looked at 308 sib-pairs from the US and reported linkage to markers on chromosomes 5p13, 6q12, 16p13, and 17p11 (Fisher et al., 2002; Ogdie et al., 2003, 2004). A second assessed 126 Dutch sib-pairs and reported linkage to chromosomes 7p13, 9q33, 13q33, and 15q15 (Bakker et al., 2003). The third looked at 16 multigenerational and extended pedigrees with densely segregated ADHD from Colombia. Linkage analysis in these families points to regions on chromosomes 4q13, 5q33, 11q22, and 17p11 (Arcos-Burgos et al., 2004b). A fourth study looked at 229 German sib-pairs and found linkage at 5p13, 6q, 7p, 9q, 11q, 12q, and 17p (Hebebrand et al., 2006). It is important to note that several regions overlap: 5p13, 6q, 9q, 11q, and 17p11. Such overlap between datasets indicates that these regions may harbor true ADHD loci. As for the other loci, the fact that the data have not been replicated could be interpreted to mean that there is genetic heterogeneity (no one major gene for ADHD) or that perhaps each population has a different genetic cause for ADHD. It is interesting to note that in the first ADHD linkage genome scan published that only 7 of 36 possible known candidate genes were not discounted (Fisher et al., 2002). Regardless, further fine mapping for all the above loci and the accumulation of more families for genetic analysis and possible further refinement of the phenotype can converge in the identification of novel candidate genes.
Gene x Environment Interactions (G x E)
An additional approach outside of candidate gene association studies and linkage analysis is to consider G x E. This is a more recent approach that has yielded some interesting data. In theory, one can utilize any biologically plausible candidate gene and look for its interaction with a candidate environmental risk on influencing the phenotype. Ideally, both the specific gene(s) and risk(s) will have much stronger connections with a disorder than previously thought, within vulnerable groups (Moffitt, Caspi, & Rutter, 2005). Several studies have already begun to look at specific candidate genes and risks as they relate to ADHD. These studies are quite recent and focus on both different genes and environmental risks. While interesting and certainly worth further investigation, no firm conclusions can yet be made. One group looked at adverse childhood environment and a functional polymorphism of 5-HTT and its impact on ADHD psychopathology in young adult delinquents and found a significant G x E interaction, indicating that carriers of at least one 5-HTT short allele are more sensitive to childhood environment adversity than carriers of the LL-genotype (Retz et al., 2007a). One group analyzed the influence of the genotypes of the NET, the COMT, and 5-HTTand adverse life events on severity of ADHD symptoms and found that 5-HTT may be involved in some features of the illness and act as a moderator of environmental influences in ADHD (Muller et al., 2008); however, an earlier study on COMT and NET psychosocial adversity in childhood found no G x E interactions (Retz et al., 2007b). Other studies have looked at the DAT1 gene. Adolescents homozygous for the 10-repeat allele or 6-repeat allele of the VNTR polymorphism who grew up in greater psychosocial adversity exhibited significantly more inattention and hyperactivity–impulsivity than adolescents with other genotypes or who lived in less adverse family conditions, suggesting a DAT1 effect only in those individuals exposed to psychosocial adversity (Laucht et al., 2007). Child hyperactivity–impulsivity and oppositional behaviors were associated with a DAT polymorphism but only when the child also had exposure to maternal prenatal smoking (Kahn, Khoury, Nichols, & Lanphear, 2003). Additionally, interaction between DAT1 genotypes and maternal use of alcohol during pregnancy suggests that DAT1 moderates the environmental risk (Brookes et al., 2006b). Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with the ADHD combined subtype (Neuman et al., 2007). CHRNA4 gene polymorphisms were tested for interactions with prenatal smoking exposure on risk for ADHD subtypes using an exon 5 polymorphism and demonstrated a significant interaction with history of maternal smoking during pregnancy for increasing risk for severe combined type ADHD (Todd & Neuman, 2007). A more recent study tested for interaction between gene variants in DRD4, DAT1, DRD5, and 5-HTT and associations with ADHD and maternal smoking, alcohol use during pregnancy and birth weight. No effects of G x E on ADHD diagnosis were observed (Langley et al., 2008). However, the results do suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and CD). Finally, G x E interactions were found for DRD2 genotypes and mother's marital status and number of marriages or cohabiting relationships (Waldman, 2007). In a more restricted cohort of individuals with early-onset antisocial behavior accompanied by ADHD, a significant G x E with COMT genotype and birth weight was identified, and those possessing the Val/Val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight (Thapar et al., 2005). However, when a second study tried to replicate these findings, they found no significant main effects of COMT genotype and birth weight or interaction effects on conduct disorder in children with ADHD (Sengupta et al., 2006). Yet another study found an interaction between the season of birth and the DRD4*7R allele in children with ADHD and conduct disorder (Seeger, Schloss, Schmidt, Ruter-Jungfleisch, & Henn, 2004). Thus, while some reports show evidence for G x E interactions and ADHD, they cannot always be replicated, but further study is certainly warranted.
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Conclusion |
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TopAbstractIntroductionComplexities in Defining the...Complexities in Studying...Finding the ADHD gene(s)ConclusionGlossaryReferences |
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Psychologists, psychiatrists, and geneticists have been working together to better understand the etiology of ADHD so that we may better identify, treat, and support these individuals and their families. The scientific research over the past 30 years reviewed in this article, has helped characterize the biological and more specifically the genetic components involved in ADHD. However, the specific genetic causes of ADHD still remain unknown. Several different things can be done that may help to better define these genetic causes. First, the recruitment (or sharing between investigators) of more families to increase the statistical power for linkage and association studies would be helpful. Second, standard measures to define and diagnose ADHD across cultures would help in meta-analysis and family studies. Third, since the phenotypic definition of ADHD is so crucial for gene finding strategies, a consensus for how to subtype or cluster ADHD would be beneficial. Clustering based directly on the response items of symptoms may be better for such strategies than subtyping. Finally, considering G x E interactions may also help in defining the etiology of ADHD. Such efforts in future studies will help to identify genes with major effects. Understanding the contribution of genes to the phenotype and their interplay with specific medications will help lead to personalized medicine to benefit children and adults with ADHD.
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Glossary |
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TopAbstractIntroductionComplexities in Defining the...Complexities in Studying...Finding the ADHD gene(s)ConclusionGlossaryReferences |
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Assortative mating: when individuals tend to mate with other individuals that are like themselves in some respect (positive assortative mating) or dissimilar (negative assortative mating). In evolution, these two types of assortative mating have the effect of reducing and expanding the range of variation, respectively, when the assorting is cued on heritable traits.
Bilineality: inheritance of a property or trait through both maternal and paternal line.
Cosegregate: when traits or markers are inherited together more often than expected based on chance alone.
Epistasis: the interaction between genes such that the action of one gene is modified by one or several other genes.
Genetic heterogeneity: multiple genes or alleles causing the same disorder in different individuals.
Penetrance: the proportion of individuals carrying a particular variation of a gene that also express a particular phenotype.
Phenocopy: when an individual's phenotype under a particular environmental condition is identical to the one of another individual whose phenotype is determined by the genotype.
Pleiotropy: when a single gene influences multiple phenotypic traits.
Conflicts of interest: None declared.
Received November 30, 2007; revision received April 24, 2008; accepted April 26, 2008
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