Abstract
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS) have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of several processes important for synaptic function. Therefore, we applied a functional gene-set analysis to formally test whether synaptic functions are associated with ADHD. Gene-set analysis tests the joint effect of multiple genetic variants in groups of functionally related genes. This method provides increased statistical power compared to conventional GWAS. We used data from the Psychiatric Genomics Consortium including 896 ADHD cases and 2455 controls, and 2064 parent-affected offspring trios, providing sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, our results do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD.
Highlights
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders
Power analyses showed that for gene sets containing on average single nucleotide polymorphism (SNP) with a risk allele frequency (RAF) of at least 0.1, our sample had sufficient power (0.80) to detect gene sets with a genotype relative risk (GRR) of 1.23 (Figure 1)
We assumed that gene sets behave as individual single nucleotide polymorphisms (SNPs)
Summary
Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. ADHD is characterized by a persistent pattern of inattention and/or impulsiveness and hyperactivity. Despite high heritability estimates for ADHD, averaging 70% [3], the identification of genes has been difficult. Most likely this is mainly due to the polygenic character of ADHD, similar to that of other complex traits, meaning that many genetic variants with small effects contribute to ADHD risk [4]. It has been reported that the top hits of GWAS point to the involvement of synaptic processes such as neurotransmission, cell-cell communication systems, potassium channel subunits and regulators, and more basic processes like neuronal migration, neurite outgrowth, spine formation, neuronal plasticity, cell division, and adhesion [6,7,8]. Many genes previously implicated in ADHD [9] are expressed in the synapse (i.e., DBH, SLC6A2, ADRA2A, HTR1B, HTR2A, TPH1/2, MAOA, CHRNA4, SNAP25, and BDNF), suggesting the involvement of synaptic function in the etiology of ADHD
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