Not in their genes: A critical view of the genetics of attention-deficit hyperactivity disorder (original) (raw)
2000, Developmental Review
https://doi.org/10.1006/DREV.2000.0511
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Abstract
This article examines evidence cited in favor of the operation of genetic factors in attention-deficit hyperactivity disorder (ADHD). Like other psychiatric conditions, a belief in the genetic basis of ADHD is derived from the results of family, twin, and adoption studies. Because ...
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Perspective on the genetics of attention deficit/hyperactivity disorder
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
This special issue of Neuropsychiatric Genetics presents both a comprehensive overview of and the latest progress in the genetics of Attention Deficit/Hyperactivity Disorder (ADHD). In many ways, this issue's wide range of topics reflects how genetics and our understanding of ADHD have developed over the course of the last 25 years. This issue includes the phenotypic interrogation of ADHD in families to assess heritability and the suitability of measures; linkage analysis of clinical and quantitative phenotypes; candidate gene association studies of biologically relevant hypotheses; genetic analyses of endophenotypes and comorbid disorders; gene expression in an animal model of ADHD; and, finally, a sequence of articles describing the genome-wide association scan (GWAS) from the International Multi-site ADHD Gene (IMAGE) Project. This set of articles recapitulates the major trends in the field of complex psychiatric genetics, underscoring how genetic studies of ADHD have evolved, and what approaches are needed to uncover the genetic etiology.
Molecular Genetics of Attention-Deficit/Hyperactivity Disorder
Biological Psychiatry, 2005
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:
Genetics of Attention Deficit Hyperactivity Disorder (ADHD): Recent Updates and Future Prospects
Attention deficit hyperactivity disorder (ADHD) is not only highly prevalent, persistent and impairing but also is one of the most heritable of all psychiatric disorders. As a result, ADHD has been the focus of considerable genetic research. The results of recent genetic studies are reviewed with a focus on the emerging picture and future trends. ADHD appears to be a complex disorder in which multiple genetic and environmental risks contribute to a quantitative trait. At the same time, there is growing evidence that in a proportion of cases, individually rare variants such as copy number variants may play an important causal role. The more genetic risks, both common and rare, the more extreme the trait. With increasing samples and advanced genetic methods, single nucleotide polymorphism (SNPs) and copy number variants (CNVs) conferring risk for ADHD are being identified. Further study will be required before we can understand the causal significance of these findings. Increased sample size is an urgent necessity if we are to discover potentially causal variants. Non-behavioral markers of genetic risk known as endophenotypes could also play a role in parsing the phenotypic and genetic heterogeneity of ADHD as they have in other complex disorders. Genetic studies in ADHD hold the potential for refined nosology, more precise diagnosis, and differential diagnosis, improved early identification leading to novel intervention strategies and identification of innovative targets for therapeutics based on a precise understanding of disease mechanism.
The genetics of ADHD: A literature review of 2005
Current Psychiatry Reports, 2006
Investigations into the genetic basis of attention-deficit/ hyperactivity disorder (ADHD) continue to yield compelling results as candidate gene studies reveal more information about this elusive disorder. Family, twin, and adoption studies further the notion that ADHD is a highly heritable disorder with direct genetic and environmental influence. The year 2005 saw many ADHD candidate gene studies, with most focused on the catecholaminergic candidates. Although many genes were studied in 2005, a large portion of findings has been supportive of the roles of dopaminergic genes’ relationship to clinical phenotypes and drug response. These studies often require replication. Clinical implications continue to be speculative, as larger sample sizes are needed to validate findings to the general population. Further understanding of endophenotypes and the impact of comorbidities also is necessary for proper clinical intervention. Forthwith, we provide a summary of ADHD genetic studies published in 2005.
Advances in genetic studies of attention-deficit/hyperactivity disorder
Current Psychiatry Reports, 2009
Attention-defi cit/hyperactivity disorder (ADHD) is among the most common childhood-onset psychiatric disorders. Although family, twin, and adoption studies demonstrate that ADHD is a highly heritable condition, studies also suggest that genetic architecture is complex, prompting the use of more advanced methodologies such as genome-wide linkage and association studies. Although such studies are theoretically compelling, replication of these results has been inconsistent. Meta-analyses have produced more reliable results, but the associations identifi ed to date account for only a small percentage of the genetic component of ADHD. Approaches such as neuroimaging genetics and epigenetic studies are being explored to probe further the etiologic complexity of this disorder.
Mini-review on the Basic Genetic Aspects for the Attention Deficit Hyperactivity Disorder (ADHD)
Bulletin of Integrative Psychiatry
Attention deficit hyperactivity disorder (ADHD) is a common and generally inherited neuropsychiatric disorder that is present in children and adults, and it is considered a multifactorial disorder. Due to the limited effects of genes on the manifestation of the disorder, we wanted to analyze the impact of the genes SNAP25, BAIAP2, ANKK1, DAT1 on attention deficit hyperactivity disorder (ADHD) and to emphasize the importance of genetic architecture in the learning experience and the development of an individual since genes can negatively affect an individual's life. Another rationale for this study was the very well-known problem of accurately diagnosing ADHD because this is usually made through questionnaires or interviews with the patient suspected of having the disorder, which can lead to errors. The idea of genetic testing to identify the different polymorphisms of genes responsible for ADHD would make the diagnosis more accurate. As a result, we searched the databases for articles in which the authors reported the impact of the genes mentioned above. We identified a total of 12 relevant articles that were discussed throughout this article. We concluded that all the genes selected for this study were implicated in the manifestation of this disorder, only when a specific circumstance was met such as a specific ethnic group was tested, or a specific polymorphism was studied.
Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder
Journal of the American Academy of Child & Adolescent Psychiatry, 2010
Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genomewide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. Results: No genomewide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1.
Genetic and Evolutionary Contributions to the Etiology of Attention Deficit Hyperactivity Disorder
Current Genetic Medicine Reports, 2017
We review progress made concerning the participation of candidate genes in the determination of attention deficit disorder with hyperactivity (ADHD) as well as recent evidence on its genetic determination based on molecular methodology. In addition to linkage analyses, we discuss recent results obtained through genome-wide association studies (GWAS). We also discuss the genetic comorbidity estimated between ADHD and major psychiatric disorders such as schizophrenia (E), major depressive disorder (MDD), bipolar disorder (BD), and autism spectrum disorders (ASD). Furthermore, we examine both the geographical distribution of DRD4 and cross-ethnic variation of ADHD risk in Chilean children. Finally, visualizing ADHD from an evolutionary perspective, we suggest that behavioral traits such as hyperactivity, inattention, impulsivity, and sexual arousal, which play a role in ADHD could have had a high adaptive value during the early stages of the evolution of Homo sapiens but turned progressively less adaptive and more recently definitively disadvantageous. Attention deficit hyperactivity disorder (ADHD) is classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) as a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. This disorder is often associated with
Cortex, 2006
Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DβH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.
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Attention-Deficit/ Hyperactivity Disorder (ADHD) is taken for granted as a neurobiological reality (Hatt, 2009). Some studies define ADHD as a familial disorder (Faraone &Biderman, 1994. Adler, 2008. Nijmeijer, 2011). The aim of this research was to examine the presence of ADHD in parents and siblings of students with/ without ADHD. The research design was descriptivecomparative. The sample group was consisting of 136 students with/ without ADHD (aged range 6-9 years) whom were selected randomly from the elementary schools of Tehran. Students with ADHD were diagnosed by DSM-IV-TR rating scale. Chi Square test was used to analyzing data. Due to available literature, it was expected that the presence of ADHD in parents and/or siblings of students with ADHD be more than students without ADHD, but the findings of this research reveal ther between them. Also, other findings show that academic problems and other behavioral disorders in students with ADHD are more than students without ADHD.
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Genetic Epidemiology, 2000
Converging evidence from family, twin, and adoption studies points to a substantial genetic component of the etiology of attention deficit hyperactivity disorder (ADHD). These data about ADHD have motivated molecular genetic studies of the disorder, which have produced intriguing but somewhat conflicting results. Some studies have reported associations with candidate genes and others not. Our review of the literature shows that one problem facing molecular genetic studies of ADHD is that its recurrence risk to first-degree relatives is only about five times higher than the population prevalence. This suggests that, to produce consistently replicated results, molecular genetic studies should either use much larger samples or should select those families in which genes exert the largest effect. Risch [(1990a) Am J Hum Genet 46:222-228; (1990b) Am J Hum Genet 46:229-241] proved that the statistical power of a linkage study increases with the magnitude of risk ratios (λ's) computed by dividing the affection rate among each relative type to the rate of affection in the population. Our prior work suggests two dimensions of genetic heterogeneity that might be useful for selecting ADHD subjects for molecular genetic studies: comorbidity with con-2 Faraone et al.
Genetics of attention-deficit hyperactivity disorder (ADHD)
Attention-deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous syndrome which is comorbid with childhood conduct disorder, alcoholism, substance abuse, dis-social personality disorder, and affective disorders. A small but consistent overlap with autistic symptoms has also been established. Twin and family studies of ADHD show a substantial genetic heritability with little or no family environmental effect. Linkage and association studies have conclusively implicated the dopamine transporter gene (DAT1). DAT1 has also been confirmed as being associated with bipolar disorder. Remarkably, and for the first time in psychiatry, genetic markers at the DAT1 locus appear to be able to predict clinical heterogeneity because the non-conduct disordered subgroup of ADHD is associated with DAT1 whereas other subgroups do not appear to be associated. The second most well replicated susceptibility gene encodes the DRD4 dopamine receptor and many other dopamine related genes appear to be implicated. It is becoming increasingly clear that genes causing bipolar mania overlap with genes for a subtype of ADHD. The key to understanding the genetics of ADHD is to accept very considerable heterogeneity with different genes having effects in different families and in different individuals. It is too early to interpret the new wave of genome-wide association and copy number variant studies but preliminary data support the overlap with affective disorder genes and also with CNS connectivity genes likely to be involved in autism and affective disorders.
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Attention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie? We have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of...
Genetics of attention-deficit/hyperactivity disorder: current findings and future directions
Expert review of neurotherapeutics, 2013
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.
Biological Psychiatry, 2005
The high heritability of the core symptoms of attention-deficit/hyperactivity disorder (ADHD) has been repeatedly demonstrated, but few studies to date have investigated the extent to which the same genetic influences operate across development or new genes emerge at different developmental periods. Methods: We report data from a large, population-based study of approximately 4,000 twin pairs, who have been followed up from early to middle childhood. Results: Parents' ratings of ADHD symptoms showed moderate stability across the ages, which was mainly due to shared genetic influences. There was also evidence of additional genetic influences, which were not shared with those acting earlier on, emerging at later age periods. The contribution of environmental influences to the stability of the ADHD symptoms over time was small. Parents' ratings on the Conners' DSM-IV ADHD subscale at the last assessment point, at an average age of 8 years, did not show the rater contrast effects that were observed in the parents' ratings at earlier ages with briefer measures. Similar estimates of genetic and environmental influences were obtained for girls and boys. Conclusions: We discuss the implications of the findings for molecular genetic studies on ADHD symptomatology.
Genes and attention-deficit hyperactivity disorder
Clinical Neuroscience Research, 2001
In a collaborative research program on attention-de®cit hyperactivity disorder (ADHD) initiated 20 years ago at UC Irvine, we adopted Cantwell's (1994) approach to de®ne a re®ned phenotype for use in studies of the biological bases of this disorder. We have used this re®ned phenotype (ADHD-Combined Type without internalizing comorbidities) in our molecular genetic studies of ADHD, which have paralleled the emerging literature in this new ®eld. In our research program, we used the candidate gene approach, with hypotheses derived from the dopamine theory of ADHD and Posner and Raichle's (1994) theory of attention. We proposed a candidate dopamine gene (DRD4) and discovered an association with ADHD due to an increase prevalence of the`7-repeat' allele de®ned by a 48-base-pair variable number of tandem repeats in exon III. The DRD4±ADHD association has now been con®rmed by multiple groups around the world. In the next steps of our research program, we are evaluating the impact of a putative DRD4 risk allele on cognition, initiating an investigation of DNA sequence variation in DRD4 alleles, and investigating the association of ADHD with other candidate genes. Using our collaborative research program as an example, we will review the history and current status of molecular genetic studies of ADHD. q
Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype?
Genetics in medicine : official journal of the American College of Medical Genetics
Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying...
2008
There are conflicting reports suggesting that the parental origin of transmitted risk alleles may play a role in the etiology of attention deficit/ hyperactivity disorder (ADHD). A recent report by Hawi and colleagues observed a generalized paternal over-transmission of alleles associated with ADHD. This was not replicated in more recent studies. Using data from a large multicenter study we examined the overall and genespecific parent of origin effect in 554 independent SNPs across 47 genes. Transmission disequilibrium and explicit parent of origin test were performed using PLINK. Overall parent of origin effect was tested by Chi-square. There was no overall parent of origin effect in the IMAGE sample (x 2 1 ¼ 1:82, P ¼ 0.117). Five markers in three genes, DDC, TPH2, and SLC6A2 showed nominal association (P < 0.01) with ADHD combined subtype when restricted to maternal or paternal transmission only. Following the initial report by Hawi and co-workers three studies, including this one, found no evidence to support an overall parent of origin effect for markers associated with ADHD. We cannot however, exclude gene-specific parent of origin effect in the etiology ADHD.
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