Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: Genome‐wide association study of both common and rare variants

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case–control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein–Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology.

Case–Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder

“…The genome-wide significance threshold was calculated by considering the three ADHD clinical subtypes and was set at Po1.7e À 08 (5e À 08/3). The phenotypic variance explained by all autosomal SNPs for ADHD was calculated with GCTA software (Yang et al, 2013). The gene-based association analysis was performed with the VEGAS software following the default settings and considering the HaMap CEU samples to estimate the linkage disequilibrium (LD) structure (Liu et al, 2010 Carlson et al, 2004).…”

“…This situation, along with advances in high-throughput technologies, stimulated a turn towards genome-wide association studies (GWAS). To date, GWAS of ADHD have been completed in seven independent datasets, six of which used pediatric samples (Franke et al, 2009;Hinney et al, 2011;Lesch et al, 2008;Mick et al, 2010;Neale et al, 2008;Neale et al, 2010a;Stergiakouli et al, 2012;Yang et al, 2013). None of them reported genome-wide significant associations and, apart from the possible involvement of cadherin 13 (CDH13) identified in three reports (Lesch et al, 2008;Neale et al, 2008;Neale et al, 2010a), there is limited overlap between them or with previous linkage or candidate gene association studies.…”

“…Four additional casecontrol GWAS were also conducted in childhood ADHD and unscreened controls. Neale et al, genotyped 896 cases and 2455 controls and found CDH13 and PRKG1 among the top-ranked genes nominally associated with ADHD, while the other three studies yielded no significant evidence of association neither in the discovery cohort nor in the replication attempts on different datasets (Hinney et al, 2011;Neale et al, 2010a;Stergiakouli et al, 2012;Yang et al, 2013). Finally, a single GWAS analysis has been reported on persistent ADHD.…”

White Matter Microstructural Alterations in Children with ADHD: Categorical and Dimensional Perspectives

“…Brain imaging studies have identified alterations in both gray matter and white matter in the brain in patients with ADHD (Thapar and Cooper, 2015). Findings from recent genetic studies also support the involvement of white matter alterations in ADHD, as genes involved in neuronal migration, axonal guidance, and myelination have been repeatedly found amongst the tophits in hypothesis-free, genome-wide gene-finding studies (Poelmans et al, 2011;Thapar and Cooper, 2015;Yang et al, 2013).…”

Environmental and Genetic Influences in Attention Deficit Hyperactivity Disorder (ADHD) and its Comorbidities

“…Common genetic factors with small effects sizes, rare variations with larger effect sizes (such as copy number variations [CNVs]) and very rare chromosomal anomalies, with even bigger effect sizes, contribute to the disorder in the population (2,134) (Fig. 3).…”