Genetics of adult attention-deficit/hyperactivity disorder.

Results of behavioral genetic investigations using family twin and adoption studies converge with those of molecular genetic studies in showing that genes influence susceptibility to'attention-deficit/hyperactivity disorder (ADHD). These finding suggest that genetic mechanisms that predispose individuals to ADHD are complex. It seems likely that the disorder is caused by the combined actions of several genes. It is equally clear that aberrant genes create a vulnerability to the disorder that is not expressed in all environments. The literature about the genetics of adult ADHD is relatively small, but it suggests not only that the persistent form of ADHD is familial, but that it is more familial than the nonpersistent form.More work from twin and molecular genetic studies is needed to determine if the increased familiality of persistent ADHD reflects the actions of genes or of familial environmental causes.     

Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20–50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.     

Genetic influences on attention deficit hyperactivity disorder

In this article we review behavioral and molecular genetics studies of attention deficit hyperactivity disorder (ADHD). Family, twin, and adoption studies, along with segregation analyses and molecular genetic studies, all support the hypothesis that both genetic and environmental factors contribute to the etiology of ADHD. Despite this strong evidence for the familial transmission of ADHD, the mode of transmission requires further clarification. In addition, because ADHD appears to be genetically heterogeneous, more work is needed to delineate genetically homogeneous subtypes and describe the range of expression of their underlying genotypes.     

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.     

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.     

Neuroanatomical abnormalities in adolescents with attention-deficit/hyperactivity disorder

ObjectiveSeveral neuroanatomic abnormalities have been reported in patients with attention-deficit/hyperactivity disorder (ADHD). However, findings are not always consistent, perhaps because of heterogeneous subject samples. Studying youths with documented familial ADHD provides an opportunity to examine a more homogeneous population.MethodTwenty-four youths with a confirmed history of familial ADHD and 10 control youths underwent high-resolution structural magnetic resonance imaging examinations. Archived magnetic resonance imaging scan data from 12 control youths were included in the analysis to increase statistical power. Individually drawn region-of-interest methods were used to examine the frontal lobe gyri and caudate.ResultsCerebral total tissue was similar between groups. The volumes of the right caudate and right inferior frontal lobe were larger in the ADHD youths compared with the control youths. Data from a subgroup of the ADHD youths suggest that increasing left caudate volume is associated with decreasing functional activation of this region.ConclusionsBecause previous studies have focused primarily on younger subjects or used an extended age range, the present results may reflect neurodevelopmental changes specific to late adolescence in familial ADHD.     

The genetics of pediatric-onset bipolar disorder.

Although bipolar disorder in adults has been extensively studied, early-onset forms of the disorder have received less attention. We review several lines of evidence indicating that pediatric- and early adolescent-onset bipolar disorder cases may prove the most useful for identifying susceptibility genes. Family studies have consistently found a higher rate of bipolar disorder among the relatives of early-onset bipolar disorder patients than in relatives of later-onset cases, which supports the notion of a larger genetic contribution to the early-onset cases. Comorbid pediatric bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) may also define a familial subtype of ADHD or bipolar disorder that is strongly influenced by genetic factors and may, therefore, be useful in molecular genetic studies. There are no twin and adoption studies of pediatric bipolar disorder, but the heritability of this subtype is expected to be high given the results from family studies. Thus, pediatric- and early adolescent-onset bipolar disorder may represent a genetically loaded and homogeneous subtype of bipolar disorder, which, if used in genetic linkage and association studies, should increase power to detect risk loci and alleles.     

Recent advances in structural and functional brain imaging studies of attention-deficit/hyperactivity disorder

The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naïve, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD.     

Magnetic resonance imaging of boys with attention-deficit/hyperactivity disorder and their unaffected siblings

OBJECTIVE: To study the influence of increased familial risk for attention-deficit/hyperactivity disorder (ADHD) on brain morphology. METHOD: Volumetric cerebral measures based on whole brain magnetic resonance imaging scans from 30 boys with ADHD, 30 of their unaffected siblings, and 30 matched controls were compared. RESULTS: Both subjects with ADHD and their unaffected siblings displayed reductions in right prefrontal gray matter and left occipital gray and white matter of up to 9.1% (p < 0.05). Right cerebellar volume was reduced by 4.9% in subjects with ADHD (p = 0.026) but not in their unaffected siblings (p = 0.308). A 4.0% reduction in intracranial volume was found in subjects with ADHD (p = 0.031), while a trend was observed in their unaffected siblings (p = 0.068). CONCLUSIONS: The volumetric reductions in cortical gray and white matter in subjects with ADHD are also present in their unaffected siblings, suggesting that they are related to an increased familial risk for the disorder. In contrast, the cerebellum is unaffected in siblings, suggesting that the reduction in volume observed in subjects with ADHD may be more directly related to the pathophysiology of this disorder.     

Attention-deficit/hyperactivity disorder: a selective overview.

Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial and clinically heterogeneous disorder that is associated with tremendous financial burden, stress to families, and adverse academic and vocational outcomes. Attention-deficit/hyperactivity disorder is highly prevalent in children worldwide, and the prevalence of this disorder in adults is increasingly recognized. Studies of adults with a diagnosis of childhood-onset ADHD indicate that clinical correlates--demographic, psychosocial, psychiatric, and cognitive features--mirror findings among children with ADHD. Predictors of persistence of ADHD include family history of the disorder, psychiatric comorbidity, and psychosocial adversity. Family studies of ADHD have consistently supported its strong familial nature. Psychiatric disorders comorbid with childhood ADHD include oppositional defiant and conduct disorders, whereas mood and anxiety disorders are comorbid with ADHD in both children and adults. Pregnancy and delivery complications, maternal smoking during pregnancy, and adverse family environment variables are considered important risk factors for ADHD. The etiology of ADHD has not been clearly identified, although evidence supports neurobiologic and genetic origins. Structural and functional imaging studies suggest that dysfunction in the fronto-subcortical pathways, as well as imbalances in the dopaminergic and noradrenergic systems, contribute to the pathophysiology of ADHD. Medication with dopaminergic and noradrenergic activity seems to reduce ADHD symptoms by blocking dopamine and norepinephrine reuptake. Such alterations in dopaminergic and noradrenergic function are apparently necessary for the clinical efficacy of pharmacologic treatments of ADHD.     

The genetics of attention deficit/hyperactivity disorder in adults, a review

The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.     

Activation in ventral prefrontal cortex is sensitive to genetic vulnerability for attention-deficit hyperactivity disorder.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder, associated with atypical patterns of brain activation in functional imaging studies. Neuroimaging measures may serve as an intermediate phenotype in genetic studies of ADHD, as they are putatively more closely linked to gene expression than a clinical diagnosis. METHODS: We used rapid, mixed-trial, event-related functional magnetic resonance imaging (fMRI) to investigate changes in brain activation during a go no-go task in boys with ADHD, their unaffected siblings, and matched control subjects. RESULTS: On the hardest inhibitory trials in our task, children and adolescents with ADHD had lower accuracy than control subjects, whereas their unaffected siblings did not. Control subjects activated a network of regions, including ventral prefrontal and inferior parietal cortex. Both children and adolescents with ADHD and their unaffected siblings showed decreased activation in these areas, as well as fewer correlations between performance and activation. CONCLUSIONS: These findings suggest that the magnitude of activation during successful inhibitions is sensitive to genetic vulnerability for ADHD in a number of regions, including ventral prefrontal cortex. If this can be replicated in future studies, this suggests that neuroimaging measures related to inhibitory control may be suitable as intermediate phenotypes in studies investigating gene effects in ADHD.     

Testing for neuropsychological endophenotypes in siblings discordant for attention-deficit/hyperactivity disorder.

BACKGROUND: Neurocognitive deficits associated with attention-deficit/hyperactivity disorder (ADHD) might be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD. METHODS: This study administered 17 measures from prominent neuropsychological theories of ADHD (executive function, processing speed, arousal regulation and, motivation/delay aversion) in dizygotic (DZ) twin pairs discordant for ADHD and control twin pairs (ages 8-18 years) to compare performance between twins affected with ADHD (n = 266), their unaffected co-twins (n = 228), and control children from twin pairs without ADHD or learning difficulties (n = 332). RESULTS: The ADHD subjects show significant impairment on executive function, processing speed, and response variability measures compared with control subjects. Unaffected co-twins of ADHD subjects are significantly impaired on nearly all the same measures as their ADHD siblings, even when subclinical symptoms of ADHD are controlled. CONCLUSIONS: Executive function, processing speed, and response variability deficits might be useful endophenotypes for genetic studies of ADHD.     

Recent developments in the genetics of attention‐deficit hyperactivity disorder

Attention‐deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder that affects children and adults. ADHD is one of the psychiatric disorders with the strongest genetic basis according to familial, twin, and single nucleotide polymorphisms (SNP)‐based epidemiological studies. In this review, we provide an update of recent insights into the genetic basis of ADHD. We discuss recent progress from genome‐wide association studies (GWAS) looking at common variants as well as rare copy number variations. New analysis of gene groups, so‐called functional ontologies, provide some insight into the gene networks afflicted, pointing to the role of neurodevelopmentally expressed gene networks. Bioinformatic methods, such as functional enrichment analysis and protein–protein network analysis, are used to highlight biological processes of likely relevance to the etiology of ADHD. Additionally, copy number variations seem to map on important pathways implicated in synaptic signaling and neurodevelopment. While some candidate gene associations of, for example, neurotransmitter receptors and signaling, have been replicated, they do not seem to explain significant variance in recent GWAS. We discuss insights from recent case–control SNP–GWAS that have presented the first whole‐genome significant SNP in ADHD.     

Molecular genetics of attention-deficit/hyperactivity disorder.

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.     

Attention-deficit disorder and conduct disorder in girls: evidence for a familial subtype.

BACKGROUND: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) raises the possibility that ADHD+CD is a distinct and separate condition. METHODS: We tested hypotheses about patterns of familial association between ADHD, CD, oppositional defiant disorder (ODD) and adult antisocial personality disorder (ASPD). Using family study methodology in a sample of girls, we found 11 children with diagnoses of ADHD+ CD, 39 with ADHD+ODD, and 90 with ADHD only. These were compared with 122 non-ADHD, non-CD control probands. Familial risk analysis was utilized. RESULTS: Relatives of each ADHD proband subgroup were at significantly greater risk for ADHD, and the relatives of ADHD-only subjects were at a greater risk of ODD than relatives of control subjects. Also, rates of CD were elevated among relatives of ADHD+CD probands only, and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between ADHD and antisocial spouses. Both ADHD and antisocial disorders occurred in the same relatives more often than expected by chance. CONCLUSIONS: These findings suggest that ADHD with and without antisocial disorders may be etiologically distinct disorders and provide evidence for the nosologic validity of ICD-10 hyperkinetic conduct disorder.     

Genetics of attention deficit hyperactivity disorder

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention deficit hyperactivity disorder (ADHD). Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. In contrast to a handful of genome-wide scans conducted thus far, many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effects. These small effects emphasize the need for future candidate gene studies to implement strategies that will provide enough statistical power to detect such small effects.     

Childhood attention deficit hyperactivity disorder features in adult mood disorders

A significant overlap between childhood mood disorders and many aspects of attention deficit hyperactivity disorder (ADHD) has been established. High rates of co-occurrence, familial aggregation, and more severe clinical manifestations of the illnesses when they are comorbid suggest that common genetic and environmental factors may contribute to the development of both disorders. Research on the co-occurrence of childhood ADHD and mood disorders in childhood has been conducted. We retrospectively investigated childhood ADHD features in adults with mood disorders. Childhood ADHD features were measured with the Korean version of the Wender Utah Rating Scale (WURS). The sample consisted of 1305 subjects: 108 subjects were diagnosed with bipolar disorder type I, 41 with bipolar disorder type II, 101 with major depressive disorder, and 1055 served as normal controls. We compared total WURS scores as well as scores on 3 factors (impulsivity, inattention, and mood instability and anxiety) among the 4 different diagnostic groups. The 4 groups differed significantly from one another on all scores. The group with bipolar disorder type II obtained the highest total scores on the WURS. The impulsivity and inattention associated with childhood ADHD were more significantly related to bipolar disorder type II than with bipolar disorder type I. The mood instability and anxiety associated with childhood ADHD seem to be significantly related to major depressive disorder in adulthood. In conclusion, multifactorial childhood ADHD features were associated with mood disorders of adulthood.     

Neurobiology of attention-deficit hyperactivity disorder

Attention-deficit hyperactivity disorder (ADHD) is an early-onset, clinically heterogeneous disorder of inattention, hyperactivity, and impulsivity. Family, twin, adoption, segregation analysis, and molecular genetic studies show that is has a substantial genetic component. Although their results are still tentative, molecular genetic studies suggest that three genes may increase the susceptibility to ADHD: the D4 dopamine receptor gene, the dopamine transporter gene, and the D2 dopamine receptor gene. Studies of environmental adversity have implicated pregnancy and delivery complications, marital distress, family dysfunction, and low social class. The pattern of neuropsychological deficits found in ADHD children implicate executive functions and working memory; this pattern is similar to what has been found among adults with frontal lobe damage, which suggests that the frontal cortex or regions projecting to the frontal cortex are dysfunctional in at least some ADHD children. Moreover, neuroimaging studies implicate frontosubcortical pathways in ADHD. Notably, these pathways are rich in catecholamines, which have been implicated in ADHD by the mechanism of action of stimulants—the class of drugs that effectively treats many ADHD children. Yet human studies of the catecholamine hypothesis of ADHD have produced conflicting results, perhaps due to the insensitivity of peripheral measures.     

Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children

OBJECTIVE: Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). To date, the impact of iron deficiency, RLS and familial history of RLS on ADHD severity has been scarcely examined in children. These issues are addressed in the present study. METHODS: Serum ferritin levels, familial history of RLS (diagnosed using National Institutes of Health (NIH) criteria) and previous iron supplementation in infancy were assessed in 12 ADHD+RLS children, 10 ADHD children and 10 controls. RLS was diagnosed using NIH-specific pediatric criteria, and ADHD severity was assessed using the Conners' Parent Rating scale. RESULTS: ADHD symptom severity was higher, although not significantly, in children with ADHD+RLS compared to ADHD. The mean serum ferritin levels were significantly lower in children with ADHD than in the control group (p<0.0005). There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores. CONCLUSIONS: Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.