Genetics of attention deficit hyperactivity disorder

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.Attention deficit hyperactivity disorder (ADHD) is a childhood-onset condition with impairing symptoms of inattention, impulsivity, and hyperactivity. Decades of research have documented and replicated key facts about the disorder (for a review, see ref.[1]). It occurs in about 5% of children with little geographic or cross-cultural variation in prevalence and often co-occurs with other conditions, including mood, anxiety, conduct, learning, and substance use disorders. Longitudinal studies show that two-thirds of ADHD youth will continue to have impairing symptoms of ADHD in adulthood. People with ADHD are at risk for a wide range of functional impairments: school failure, peer rejection, injuries due to accidents, criminal behavior, occupational failure, divorce, suicide, and premature death. Although many details of ADHD's pathophysiology are unknown, neuropsychological and neuroimaging studies implicate brain circuits regulating executive functioning, reward processing, timing, and temporal information processing.This article reviews data about the role that genes play in the etiology of ADHD from two perspectives. Family, twin, and adoption studies provide a firm foundation for asserting that genes are involved in the etiology of ADHD. The view from molecular genetics provides a basis for understanding mechanisms whereby genes affect biological pathways that lead to ADHD. Family, twin and adoption studies of ADHDEvidence for heritability from family, adoption, and twin studies A study of 894 ADHD probands and 1135 of their siblings aged 5-17 years old found a ninefold increased risk of ADHD in siblings of ADHD probands compared with siblings of controls [2]. Adoption studies suggest that the familial factors of ADHD are attributable to genetic factors rather than shared environmental factors [3,4] with the most recent one reporting rates of ADHD to be greater among biological relatives of non-adopted ADHD children than adoptive relatives of adopted ADHD children. The adoptive relatives had a risk for ADHD like the risk in relatives of control childr...

Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes

“…Brainimaging studies have identified various different regions, such as the cerebellum and frontal cortex, to be implicated in ADHD 3,4 . Twin studies have estimated the narrow-sense heritability of ADHD to be approximately 70%, suggesting a strong genetic component is driving the phenotypic variance 5 . Recently, a large-scale genome-wide association study (GWAS) identified several loci that were significantly associated with ADHD 6 .…”

ADHD: strategies to unravel its genetic architecture

“…Family-genetic studies indicate that ADHD aggregates in families, with a 5-8 fold increased risk in first-degree relatives and a 2-fold increased risk in second-degree relatives (Faraone et al, 1994). Twin studies found evidence for a narrow additive heritability of 0.75 to 0.91 which was robust across familial relationships and across definitions of ADHD as the end of a continuum or as a disorder with various symptom cutoffs (Levy et al, 1997;Sherman et al, 1997).…”

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

“…ADHD is a multifactorial disorder with heritability averaging 76% throughout the lifespan [3][4][5] . There is consistent evidence that both common and rare variants make an important contribution to the risk for the disorder [6][7][8][9][10][11] . Several genome-wide association studies (GWAS) and meta-analyses across those have been conducted 7 , but only the largest GWAS meta-analysis (GWAS-MA) performed to date, including 20,183 ADHD patients and 35,191 controls, reported genome-wide significant loci (N=12) 6 .…”