Abstract
Background:Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder of the neuro-developmental type, marked by an ongoing pattern of inattention or hyperactivity/impulsivity, which interferes with functioning or development. The disorder affects approximately 5-7 % children and 2-5 % of adults worldwide. Numerous studies have indicated that genetic factors predominate the causes for ADHD. Nevertheless, no systematic study has summarized these findings and provided an objective and complete list of genes with a reported association to ADHD. Methods:Literature and enrichment metrics analyses were used to discover genes of specific significance associated with ADHD. We conducted a literature data mining (LDM) of over 2,410 articles covering publications from Jan. 1988 to Apr. 2016, where 235 genes were reported to be associated with the disease. Then we performed a gene set enrichment analysis (GSEA) and a sub-network enrichment analysis (SNEA) to study the functional profile and pathogenic significance of these genes associated with ADHD. Lastly, we performed a network connectivity analysis (NCA) to study the associations between the reported genes. Results:181/235 genes enriched 100 pathways (p<1.1e-007), demonstrating multiple associations with ADHD. Twelve genes were discovered to be associated with ADHD, in terms of both functional diversity and replication frequency, including SLC6A3, DRD4, BDNF, DRD2, HTR2A, DBH, HTR1B, DRD5, GRM7, DRD3, TH and GRIN2A. In addition, one novel gene, SHANK2, was suggested worthy of further study. Moreover, SNEA and NCA results indicated that many of these genes form a functional network, playing roles in the pathogenesis of other ADHD related disorders. Conclusion:Our results suggest that the genetic causes of ADHD are linked to a genetic and functional network composed of a large group of genes. The gene lists, together with the literature and enrichment metrics provided in this study, could serve as groundwork for further biological/genetic studies in the field
Highlights
Attention deficit hyperactivity disorder (ADHD) is a brain disorder characterized by problems in paying attention, excessive activity, or difficulty in controlling behavior that is inappropriate for a person's age.[1]. The World Health Organization estimated that it affected around 39 million people as of 2013.(2) ADHD is diagnosed approximately three times more in boys than in girls.[3]. Despite being the most commonly studied and diagnosed psychiatric disorder in children and adolescents, the cause for the disorder remains unknown in majority of the cases
Instead of focusing on a specific gene, we attempt to provide a full view of the genetic-map, and use gene set enrichment analysis (GSEA), as well as a sub-network enrichment analysis (SNEA) to study the underlying functional profile of the genes identified.[15]. We hypothesized that the majority of these previously reported genes, if not all of them, play roles in the development of ADHD, and that the major pathways/gene sets enriched by these genes are the ones associated with the disease
network connectivity analysis (NCA) and enrichment analysis results suggested that these genes play significant roles as a network in the pathogenesis of ADHD, operating as a functional genetic network influencing the development of ADHD
Summary
Attention deficit hyperactivity disorder (ADHD) is a brain disorder characterized by problems in paying attention, excessive activity, or difficulty in controlling behavior that is inappropriate for a person's age.[1]. There have been an increased number of articles reporting hundreds of genes/proteins related to ADHD, many of which have been suggested as potential biomarkers for the disease, such as SLC6A3 and ADRA2A. Hong et al showed that differential expressions of Homer 1a and Homer 2a/b, a family of scaffolding proteins localized to the postsynaptic density of glutamatergic excitatory synapses, were observed in the prefrontal cortex and extended to the hippocampus. These genes have direct connections to attention and cognition, the two functions that were disturbed in ADHD.
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