From rare Copy Number Variations to biological processes in ADHD

Abstract

AimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.MethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.ResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants.ConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

From Man to Fly–convergent Evidence Links Fbxo25 to Adhd and Comorbid Psychiatric Phenotypes

“…One of the two genes, FBXO25, has an orthologue in Drosophila melanogaster, and we were able to confirm that its overexpression, as expected to arise from a copy number gain, leads to a nightspecific increase in locomotor activity and decrease in sleep. Since we have previously identified the same behavioral signature in several Drosophila models of ADHD (van der Voet et al, 2016) and similar phenotypes have also been suggested as readout for mania and circadian dysregulation (Guo et al, 2018;Padiath et al, 2004;Ries et al, 2017), these findings support FBXO25 as a novel risk gene for ADHD and comorbid mental disorders.…”

“…Among the behaviors that can be robustly assessed in Drosophila are locomotor activity and sleep, which are known to undergo a well-regulated day/night rhythm. These phenotypes have earlier been linked to genes implicated in mania and circadian dysregulation disorders (Guo et al, 2018;Padiath et al, 2004;Ries et al, 2017). In a previous study, we also reported increased activity and decreased sleep upon knockdown of genes that have been highly implicated in ADHD, encoding the dopamine transporter, latrophilin, and neurofibromin 1 (van der Voet et al, 2016).…”

From man to fly – convergent evidence links FBXO25 to ADHD and comorbid psychiatric phenotypes

“…We queried these existing data sources and found an additional ADHD patient, among 6,176 reported ones, who carried a duplication encompassing 77% of the FBXO25 gene and including the promoter region. This duplication was not found in 25,026 controls (Elia et al, ; Harich et al, ).…”

“…The identified microduplication in 8p23.3 has not previously been reported in conjunction with ADHD or other neuropsychiatric disorders. A recent study combined data from eleven CNV studies that had identified rare CNVs occurring in patients with ADHD (Harich et al, ). We queried these existing data sources and found an additional ADHD patient, among 6,176 reported ones, who carried a duplication encompassing 77% of the FBXO25 gene and including the promoter region.…”