Advances in Molecular Genetic Studies of Attention Deficit Hyperactivity Disorder in China

By Gao, Qian; Liu, Lu et al. | General Psychiatry, August 2014 | Go to article overview

Advances in Molecular Genetic Studies of Attention Deficit Hyperactivity Disorder in China


Gao, Qian, Liu, Lu, Qian, Qiujin, Wang, Yufeng, General Psychiatry


1. Introduction

Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood-onset neuropsychiatric condition, with an estimated worldwide-pooled prevalence of 5 to 12% in school-age children [1, 2] and 2 to 5% in adults. [3] On average 50% (32.8 to 84.1%) of children with ADHD continue to meet DSM-IV criteria for ADHD as adults. [4] In China, reported prevalence ranges from 4.31 to 5.83%. [5, 6] ADHD is characterized by age-inappropriate and impaired levels of inattention, hyperactivity and impulsivity. These three primary clinical characteristics may be expressed to different extents among children with ADHD, as reflected in the DSM-IV subclassification of ADHD into primarily inattentive (ADHD-I), primarily hyperactive/impulsive (ADHD-HI), and combined (ADHD-C) subtypes. [7] The ratio of boys to girls with ADHD is between 3:1 and 9:1. ADHD is associated with prolonged dysfunction including low self-esteem, substance abuse, delinquency, and other types of psychological problems. These limitations cause a heavy burden to the individual, their families, and society.

ADHD is a complex condition caused by the interaction of genetic, social, and environmental factors. [8] Adoption and twin studies have helped disentangled the genetic and environmental sources of transmission of ADHD. A review [9] of 20 twin studies from the United States, Australia, Scandinavia, and the European Union reported a mean heritability estimate of 76%, indicating that ADHD is one of the most heritable psychiatric disorders. Molecular genetics studies suggest that ADHD is a multifactorial polygenic disorder with minor contribution from each individual susceptibility gene. Multiple neural pathways have been implicated in the development of ADHD including the dopaminergic, norepinephrinergic, serotonergic, and cholinergic pathways. [10] Current findings from both candidate gene studies and genome-wide association studies (GWAS) have failed to find a major gene for ADHD.

The present review introduces the Chinese contribution to the molecular genetics of ADHD. Three English databases (PubMed, Embase, Google Scholar) and one Chinese database (CNKI) were searched for relevant reports published prior to June 2014. The medical subject heading terms and/or text words used for the search were as follows: 'attention deficit hyperactivity disorder' or 'ADHD' or 'ADD' or 'attention deficit' or 'hyperactivity' or 'hyperkinetic syndrome' AND 'genetic' or 'polymorphism' or 'gene'. Identified studies were selected if they were conducted in mainland China, Hong Kong, or Taiwan. The reference lists of selected studies were reviewed to identify any additional studies and additional papers from China not identified in the search but considered relevant by the authors. Based on these published reports, our review starts with an overview of candidate gene studies, considers ADHD endophenotypes, presents results from the first GWAS of ADHD in Chinese Han children, and concludes with a discussion of pharmacogenomics studies.

2. Candidate gene studies

2.1 Dopaminergic system (DA system)

The dopaminergic theory, proposed by Levy, [11] suggests that DA deficits in specific brain regions, such as cortical areas and the striatum, results in ADHD symptoms. Supporting evidence from animal model studies and from pharmacology, brain imaging, and genetic studies has made the dopaminergic theory the most popular theory about the genetic etiology of ADHD. [12]

2.1.1 Dopamine transporter genes (DAT, SLC6A3)

The dopaminergic theory about the neurobiology of ADHD led to the first gene association study for ADHD by Cook and colleagues. [13] They investigated a 40 bp variable number tandem repeats (VNTR) located in the 3' untranslated region (3'UTR) of the dopamine transporter gene (DAT1) in ADHD families. Using the family-based haplotype relative risk (HRR) measure, an association with the 10-repeat allele (10R) was detected. …

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