A review on cognitive and brain endophenotypes that may be common in autism spectrum disorder and attention-deficit/hyperactivity disorder and facilitate the search for pleiotropic genes
01 May 2011-Neuroscience & Biobehavioral Reviews (PERGAMON-ELSEVIER SCIENCE LTD)-Vol. 35, Iss: 6, pp 1363-1396
TL;DR: The hitherto rather separate research fields of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are brought together, and by contrasting and combining findings of the endophenotypes of ASD and ADHD new insights can be gained into the etiology and pathophysiology of these two disorders.
About: This article is published in Neuroscience & Biobehavioral Reviews.The article was published on 2011-05-01. It has received 393 citations till now. The article focuses on the topics: Developmental disorder & Autism spectrum disorder.
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TL;DR: From studies of copy number variants, it is learned that the rare insertions or deletions account for part of ADHD’s heritability, which has implicated new biological pathways that may eventually have implications for treatment development.
Abstract: Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD’s high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD’s heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD’s heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
612 citations
TL;DR: It is argued that deficits in executive functioning, theory of mind, and central coherence can all be understood as the consequence of a core deficit in the flexibility with which people with autism spectrum disorder can process violations to their expectations.
Abstract: There have been numerous attempts to explain the enigma of autism, but existing neurocognitive theories often provide merely a refined description of 1 cluster of symptoms. Here we argue that deficits in executive functioning, theory of mind, and central coherence can all be understood as the consequence of a core deficit in the flexibility with which people with autism spectrum disorder can process violations to their expectations. More formally we argue that the human mind processes information by making and testing predictions and that the errors resulting from violations to these predictions are given a uniform, inflexibly high weight in autism spectrum disorder. The complex, fluctuating nature of regularities in the world and the stochastic and noisy biological system through which people experience it require that, in the real world, people not only learn from their errors but also need to (meta-)learn to sometimes ignore errors. Especially when situations (e.g., social) or stimuli (e.g., faces) become too complex or dynamic, people need to tolerate a certain degree of error in order to develop a more abstract level of representation. Starting from an inability to flexibly process prediction errors, a number of seemingly core deficits become logically secondary symptoms. Moreover, an insistence on sameness or the acting out of stereotyped and repetitive behaviors can be understood as attempts to provide a reassuring sense of predictive success in a world otherwise filled with error. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
542 citations
TL;DR: Prospective studies of infants at familial risk are characterizing developmental pathways to ASD and early neurocognitive markers include atypical neural response to gaze and slowed disengagement.
465 citations
Radboud University Nijmegen1, King's College London2, Heidelberg University3, Carlos III Health Institute4, State University of New York Upstate Medical University5, Karolinska Institutet6, Haukeland University Hospital7, I.M. Sechenov First Moscow State Medical University8, Autonomous University of Barcelona9, Hungarian Academy of Sciences10, Goethe University Frankfurt11
TL;DR: A severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed, and it is encouraged that large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies are encouraged.
351 citations
Radboud University Nijmegen Medical Centre1, State University of New York Upstate Medical University2, King's College London3, Universidade Federal do Rio Grande do Sul4, American Board of Legal Medicine5, University of Massachusetts Medical School6, Haukeland University Hospital7, University of Bergen8, University of Würzburg9, Maastricht University10, University of Barcelona11
TL;DR: Progress in identifying aADHD risk genes may provide tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.
Abstract: 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.
346 citations
References
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TL;DR: The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
Abstract: Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
5,321 citations
TL;DR: A psychobiological model of the structure and development of personality that accounts for dimensions of both temperament and character is described, for the first time, for three dimensions of character that mature in adulthood and influence personal and social effectiveness by insight learning about self-concepts.
Abstract: In this study, we describe a psychobiological model of the structure and development of personality that accounts for dimensions of both temperament and character. Previous research has confirmed four dimensions of temperament: novelty seeking, harm avoidance, reward dependence, and persistence, which are independently heritable, manifest early in life, and involve preconceptual biases in perceptual memory and habit formation. For the first time, we describe three dimensions of character that mature in adulthood and influence personal and social effectiveness by insight learning about self-concepts. Self-concepts vary according to the extent to which a person identifies the self as (1) an autonomous individual, (2) an integral part of humanity, and (3) an integral part of the universe as a whole. Each aspect of self-concept corresponds to one of three character dimensions called self-directedness, cooperativeness, and selftranscendence, respectively. We also describe the conceptual background and development of a self-report measure of these dimensions, the Temperament and Character Inventory. Data on 300 individuals from the general population support the reliability and structure of these seven personality dimensions. We discuss the implications for studies of information processing, inheritance, development, diagnosis, and treatment. (Arch Gen Psychiatry. 1993;50:975-990)
4,964 citations
TL;DR: The findings suggest that geographic location plays a limited role in the reasons for the large variability of ADHD/HD prevalence estimates worldwide and that this variability seems to be explained primarily by the methodological characteristics of studies.
Abstract: Objective: The worldwide prevalence estimates of attention deficit hyperactivity disorder (ADHD)/hyperkinetic disorder (HD) are highly heterogeneous. Presently, the reasons for this discrepancy remain poorly understood. The purpose of this study was to determine the possible causes of the varied worldwide estimates of the disorder and to compute its worldwide-pooled prevalence. Method: The authors searched MEDLINE and PsycINFO databases from January 1978 to December 2005 and reviewed textbooks and reference lists of the studies selected. Authors of relevant articles from North America, South America, Europe, Africa, Asia, Oceania, and the Middle East and ADHD/HD experts were contacted. Surveys were included if they reported point prevalence of ADHD/HD for subjects 18 years of age or younger from the general population or schools according to DSM or ICD criteria. Results: The literature search generated 9,105 records, and 303 full-text articles were reviewed. One hundred and two studies comprising 171,756 ...
4,712 citations
TL;DR: The risk of having at least 1 psychiatric disorder by age 16 years is much higher than point estimates would suggest and concurrent comorbidity and homotypic and heterotypic continuity are more marked in girls than in boys.
Abstract: Results: Although 3-month prevalence of any disorder averaged 13.3% (95% confidence interval [CI], 11.7%15.0%), during the study period 36.7% of participants (31% of girls and 42% of boys) had at least 1 psychiatric disorder. Some disorders (social anxiety, panic, depression, and substance abuse) increased in prevalence, whereas others, including separation anxiety disorder and attention-deficit/hyperactivity disorder (ADHD), decreased. Lagged analyses showed that children with a history of psychiatric disorder were 3 times more likely than those with no previous disorder to have a diagnosis at any subsequent wave (odds ratio, 3.7; 95% CI, 2.94.9; P.001). Risk from a previous diagnosis was high among both girls and boys, but it was significantly higher among girls. Continuity of the same disorder (homotypic) was significant for all disorders except specific phobias. Continuity from one diagnosis to another (heterotypic) was significant from depression to anxiety and anxiety to depression, from ADHD to oppositional defiant disorder, and from anxiety and conduct disorder to substance abuse. Almost all the heterotypic continuity was seen in girls. Conclusions: The risk of having at least 1 psychiatric disorder by age 16 years is much higher than point estimates would suggest. Concurrent comorbidity and homotypic and heterotypic continuity are more marked in girls than in boys.
3,729 citations
TL;DR: It is revealed that EF deficits are consistently found in both ADHD and autism but not in CD (without ADHD) or in TS, and both the severity and profile of EF deficits appears to differ across ADHD and Autism.
Abstract: In this paper, we consider the domain of executive functions (EFs) and their possible role in developmental psychopathologies. We first consider general theoretical and measurement issues involved in studying EFs and then review studies of EFs in four developmental psychopathologies: attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), autism, and Tourette syndrome (TS). Our review reveals that EF deficits are consistently found in both ADHD and autism but not in CD (without ADHD) or in TS. Moreover, both the severity and profile of EF deficits appears to differ across ADHD and autism. Molar EF deficits are more severe in the latter than the former. In the few studies of more specific EF tasks, there are impairments in motor inhibition in ADHD but not in autism, whereas there are impairments in verbal working memory in autism but not ADHD. We close with a discussion of implications for future research.
3,108 citations