ADHD: strategies to unravel its genetic architecture

Abstract

Summary. Attention deficit=hyperactivity disorder (ADHD) is a common and impairing neuropsychiatric disorder with onset at preschool age and strong persistence over time. Its validity as a psychiatric disorder has been established according to Robins and Guze criteria. Genetic factors predominate in the etiology of ADHD. This paper summarizes the current status of genetic research into ADHD, and describes eight factors that complicate research into genetically complex disorders as ADHD. These factors are that multiple genes of small main effects are involved rather than main genes, the relevant phenotype is unknown, presence of clinical heterogeneity, presence of genetic heterogeneity, gene-environment correlation, gene-environment interaction, importance of endophenotypes, and importance of developmental factors. The further unraveling of the genetic architecture of ADHD will depend to a large extent on how well these complicating factors are handled or even used.

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

“…For both disorders, oligogenic and multifactorial modes of inheritance have been proposed, but relatively little progress has yet been made in identifying the genes involved [31, 33]. This may be (partly) due to clinical and genetic heterogeneity [55] as well as to other factors [18]. How then should we proceed in our search for common genetic risk factors for ADHD and ASD?…”

Preliminary evidence for altered motion tracking-based hyperactivity in ADHD siblings

“…Moreover, intermediate phenotypes may help characterize early predictors of ADHD that could lead to more refined treatments and primary prevention strategies [10,11]. Finally, intermediate phenotypes provide quantifiable measures that can advance genetic analysis of the disorder [7,12]. …”

Neuroanatomical Abnormalities in Adolescents With Attention-Deficit/Hyperactivity Disorder

“…The disorder is also associated with academic and interpersonal relationship problems during adolescence 3-5, and adulthood 6. A refined understanding of the neural basis of ADHD during development may lead to improved treatment that could reduce the deleterious effects of this disorder on the lives of the 3% to 7% affected school-aged children in the U.S. 7.…”

“…ADHD undoubtedly results from a wide variety of etiologies (reviews include 7, 17-19), producing variations in the neural manifestations of this behaviorally defined condition. A study including a more homogeneous sample with well-documented familial etiology would contribute to our understanding of the neural correlates of inherited forms of the disorder, as distinguished from other forms of ADHD.…”