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

Abstract

Background: Mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD), have a complex etiology, and identification of underlying genetic risk factors is challenging. This study used a multistep approach to identify and validate a novel risk gene for ADHD and psychiatric comorbidity. Methods: In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copynumber variations (CNVs) linked to disease. Genes present in the identified CNV were subsequently tested for their association with ADHD in the largest data set currently available (n = 55,374); this gene-set and gene-based association analyses were based on common genetic variants. Significant findings were taken forward for functional validation using Drosophila melanogaster as biological model system, altering gene expression using the GAL4-UAS system and a pan-neuronal driver, and subsequently characterizing locomotor activity and sleep as functional readouts. Results: We identified a copy number gain in 8p23.3, which segregated with psychiatric phenotypes in the family and was confirmed by quantitative RT-PCR. Common genetic variants in this locus were associated with ADHD, especially those in FBXO25 and TDRP. Overexpression of the FBXO25 orthologue in two Drosophila models consistently led to increased locomotor activity and reduced sleep compared with the genetic background control. Conclusions: We combine ADHD risk gene identification in an individual family with genetic association testing in a large case-control data set and functional validation in a model system, together providing an important illustration of an integrative approach suggesting that FBXO25 contributes to key features of ADHD and comorbid neuropsychiatric disorders. and Annette.Schenck@radboud umc.nl (A.S.) Key pointsIntegration of data across multiple levels can help in gene identification for psychiatric disorders. Microduplication cosegregated with different psychiatric phenotypes, ranging from learning difficulties to ADHD, psychosis, substance use, and aggressive behavior.First report providing evidence for FBXO25, a gene involved in ubiquitination, having a role in the nervous system.De novo variant in DUSP16 may have modifying role in early development of the patient's severe psychiatric phenotypes. Information about common variants may be used to support decisions about (clinical) relevance of rare genetic variants.

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

“…Beyond those involved in the actually restricted candidate region, other genes less frequently included in 8p23.2-pter microdeletions may cooperate to the clinical spectrum. Examples are CSMD1 in 8p23.2, a dosage-sensitive gene associated to ASD, schizophrenia and epilepsy [ 68 , 69 , 70 ] and FBXO25, recently associated to neuropsychiatric disorders [ 71 ]. Both genes are not included in most of the microdeletions reported to date, but they might act as phenotypic modifiers in patients with microdeletions spanning until the 8p23.2 or 8p23.3 regions, respectively.…”

Immuno-moodulin: A new anxiogenic factor produced by Annexin-A1 transgenic autoimmune-prone T cells

“…Combining all this information, it is possible to speculate that the protein has biological effects other than regulating spermatogenesis. At this regard, a very interesting study has recently shown that Tdrp is linked to mental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD) (Harich et al, 2019). The authors sought to validate the relevance of their finding in Drosophila but while they could find two orthologues for FBXO25, there was no orthologue for Tdrp.…”

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

“…MAPK signaling plays a role in different psychiatric disorders, including ADHD and autism (Poelmans et al, 2013;Vithayathil et al, 2018). Moreover, the brain relies on ubiquitination to finetune protein content in order to react to new stimuli (Hegde & van Leeuwen, 2017). Another E3 ligase, FBXO33, has been the top-finding of the first casecontrol genome-wide association study of persistent ADHD (Sanchez-Mora et al, 2015).…”