Research Review: The strength of the genetic overlap between ADHD and other psychiatric symptoms – a systematic review and meta‐analysis (original) (raw)
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Investigating the Contribution of Common Genetic Variants to the Risk and Pathogenesis of ADHD
American Journal of Psychiatry, 2012
1 8 6 a jp.p sych ia tryo n lin e.o rg A m J Psych ia try 1 6 9 :2 , Feb ru a ry 2 0 1 2 significance , although, as has repeatedly been demonstrated for other phenotypes, this can in part be overcome for at least a proportion of risk variants as larger samples become available for performing meta-analyses. For GWAS of childhood-onset psychiatric disorders, such as ADHD and autism, the types of sample sizes required, even with international collaboration, have yet to be achieved . Another possibility is that if ADHD is genetically heterogeneous (in the sense that there are multiple phenotypes with limited or no overlap at the level of common risk alleles), the effects of each allele might be diluted, resulting in lower apparent effect sizes. However, it is currently unclear how best to subdivide ADHD in a way that might overcome this problem or whether such subdivisions are possible. An alternative explanation for the negative GWAS findings might be that ADHD risk is entirely explained by multiple low-frequency variants that are not well captured by (A m J P sy c h ia try 2 0 1 2 ; 1 6 9 : in v e stig a tin g th e C o n trib u tio n o f C o m m o n G e n e tic V a ria n ts to th e r isk a n d P a th o g e n e sis o f A D H D
Case-control genome-wide association study of attention-deficit/hyperactivity disorder
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.
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.
Shared genetic background between children and adults with attention deficit/hyperactivity disorder
Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent genome-wide significant loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while...
Theoretical biology & medical modelling, 2005
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 (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.
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.
An exploratory study of links between ADHD and a chromosomal mutation in a single family
2000
Conclusion 31 Future research 34 References 35 The aim of this paper is to review evidence of genetic factors in the aetiology of Attention Deficit Hyperactivity Disorder (ADHD). The review examines our current understanding of ADHD, including behavioural criteria, development, and cognition. It is concluded that there are a number of limitations in our current understanding of ADHD, stemming from high levels of co-morbidity, qualitative differences among subtypes, variable research methodology and a heavy reliance on a top down approach to research. The research literature contains a large amount of variation in measurement associated with defining ADHD as a behavioural phenotype, hampering genetic research. It is concluded that there is strong evidence supporting a genetic component to ADHD. Family, twin and molecular studies suggest ADHD may be part of some continuum, with a number of disorders having common genetic vulnerability, and that many genes interacting with environmental variables may be involved. It is suggested that future research should be longitudinal and family based in order to link behavioural, cognitive and genetic characteristics of ADHD as they emerge across the lifespan, and thereby inform our understanding of ADHD on a number of levels. 10%-30% Continual display of core symptoms and development of serious psychopathology (eg alcohol abuse, Antisocial Personality Disorder). Adolescent Outcome Adolescence brings with it increased cognitive, academic, personal and social demands. Children with ADHD greet adolescence with pre-existing difficulties including learning gaps, poor social relationships and low self-esteem (Weiss & Hechtman, 1993). Research reveals an overall picture of children diagnosed with 8 ADHD going on to experience significant academic, social and conduct difficulties in high school (Weiss & Hechttnan, 1993), including significantly more grade retention, suspension and dropping out (Barkley, 1991). The core symptoms of inattention and impulsivity appear to abate with age, although scores on tests of both symptoms remain significantly poorer compared to scores of normal controls (Fischer, Barkley, Edelbrock & Smallish, 1990). Hyperactivity on the other hand appears to decline almost completely, with only residual restlessness apparent, such that "rebelliousness" rather than "overactivity" is the greater concern of people in the adolescent's life (Weiss & Hechtman, 1993). Evidence of continual symptoms of ADHD along with antisocial and drug abuse disorders presents the worst outcome for the adolescent (Manuzza, Klien, Bessler, Malloy & LaPadula, 1993). Adult Outcome The adult with ADHD is seen as disorganised, impatient, distractible, impulsive, easily bored, procrastinating, having poor concentration, difficulty following through, low frustration tolerance, mood swings, and low self-esteem (Cantwell, 1996; Hallowell & Ratey, 1997). Prospective studies have shown that while many children with ADHD outgrow the disorder, at least 11% (Marmit77n et al., 1993) and as many as 36% (Weiss, Hechtman, Milroy & Perlman, 1985) continue to experience at least one residual symptom of ADHD that significantly impairs their functioning. The discrepancy in these findings may be due to methodological differences, for example the study by Mannuzza et al., (1993) used parental reports while the study by Weiss et al., (1985) used self-reports. Weiss et al., (1985) found that adults with childhood ADHD had more symptoms of psychopathology, poorer social skills and lower self-esteem than 9 I
Characterizing the ADHD phenotype for genetic studies
Developmental Science, 2005
The genetic study of ADHD has made considerable progress. Further developments in the field will be reliant in part on identifying the most appropriate phenotypes for genetic analysis. The use of both categorical and dimensional measures of symptoms related to ADHD has been productive. The use of multiple reporters is a valuable feature of the characterization of psychopathology in children. It is argued that the use of aggregated measures to characterize the ADHD phenotype, particularly to establish its pervasiveness, is desirable. The recognition of the multiple comorbidities of ADHD can help to isolate more specific genetic influences. In relation to both reading disability and conduct disorder there is evidence that genes may be involved in the comorbid condition that are different from pure ADHD. To date, progress with the investigation of endophenotypes for ADHD has been disappointing. It is suggested that extending such studies beyond cognitive underpinnings to include physiological and metabolic markers might facilitate progress.