Meta-Analysis of Copy Number Variants Associated with Attention Deficit Hyperactivity Disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disease involving inattention and hyperactivity, which affects 5.4 million children worldwide with a frequency of approximately nine percent. As copy number variants (CNVs) are the largest component of genetic variation, the intuition was that they have a relatively higher chance of overlapping genes associated with ADHD and therefore are more likely to have an impact on the ADHD phenotype. This meta-analysis sought to identify and systematically classify significant associations found between ADHD and genes affected by CNVs in order to find a pattern of associations existing in the literature. The analysis demonstrated that copy number variants affected a limited number of genes, specifically 14, associated with ADHD. Although a karyotyping protocol demonstrated no clear similarity between these 14 genes in regard to their chromosomal locations, they were all classified into one of three gene ontological categories: receptor-associated, homeostatic and molecular process-associated, and disease-associated. This meta-analysis contributes to the ADHD literature through the construction of an ADHD gene annotation map. Moreover, it demonstrates that genes affected by ADHD-associated CNVs function in various cellular and neurological pathways and signifies ADHD as a complex phenotype with many determining biological factors and pathways. Since prior studies were conducted using data generated from cohorts primarily consisting of individuals with European ancestry, an attempt was made to replicate the findings using data from the ethnically diverse Fragile Families and Child Wellbeing Study (FFCWS). Some epidemiological assessments were also done to check the social and environmental influences on ADHD, such as maternal behavior during pregnancy and social disparity.