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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 copy-number 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.

SUBMITTER: Harich B

PROVIDER: S-EPMC7217029 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Harich Benjamin B Klein Marieke M Ockeloen Charlotte W CW van der Voet Monique M Schimmel-Naber Marlies M de Leeuw Nicole N Schenck Annette A Franke Barbara B

Journal of child psychology and psychiatry, and allied disciplines 20191217 5

<h4>Background</h4>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.<h4>Methods</h4>In a single family, severely affected by ADHD and cooccurring disorders, we applied single nucleotide polymorphism (SNP)-array analysis to detect copy-number variations (CNVs) ...[more]

PMID: 31849056

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Project description:BackgroundIndividuals with co-existing serious mental illness and non-psychiatric medical illness are at high risk of acute care utilization. Mining of electronic health record data can help identify and categorize predictors of psychiatric hospital readmission in this population.ObjectiveThis study aimed to identify modifiable predictors of psychiatric readmission among individuals with comorbid bipolar disorder and medical illness. This goal was accomplished by applying objective variable selection via machine learning techniques.MethodThis was a retrospective analysis of electronic health record data derived from 77,296 episodes of care from 2006 to 2016 within the University of California Health Care System. Data included 1,250 episodes of care involving patients with bipolar disorder and serious comorbid medical illnesses (defined by transfer between medicine and psychiatry services or concomitant primary medical and psychiatric admission diagnoses). Machine learning (classification trees) was used to identify potential predictors of 30-day psychiatric readmission across hospital encounters. Predictors included demographics, medical and psychiatric diagnoses, medication regimen, and disposition. The algorithm was internally validated using 10-fold cross-validation.ResultsThe model predicted 30-day readmission with high accuracy (98% unbalanced model, 88% balanced model). Modifiable predictors of readmission were length of stay, transfers between medical and psychiatric services, discharge disposition to home, and all-cause acute health service utilization in the year before the index hospitalization.ConclusionAmong bipolar disorder patients with comorbid medical conditions, characteristics of the index hospitalization (e.g., duration, transfer, and disposition) emerged as more predictive than static properties of the patient (e.g., sociodemographic factors and psychiatric comorbidity burden). Findings identified phenotypes of patients at high risk for rehospitalization and suggest potential ways of modifying the risk of early readmission.

Dataset Information

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

Publications

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

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