Transcriptomic risk scores for attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. We performed a transcriptome-wide association study (TWAS) using the latest genome-wide association study (GWAS) meta-analysis, in 38,691 individuals with ADHD and 186,843 controls, and 14 gene-expression reference panels across multiple brain tissues and whole blood. Based on TWAS results, we selected subsets of genes and constructed transcriptomic risk scores (TRSs) for the disorder in peripheral blood mononuclear cells of individuals with ADHD and controls. We found evidence of association between ADHD and TRSs constructed using expression profiles from multiple brain areas, with individuals with ADHD carrying a higher burden of TRSs than controls. TRSs were uncorrelated with the polygenic risk score (PRS) for ADHD and, in combination with PRS, improved significantly the proportion of variance explained over the PRS-only model. These results support the complementary predictive potential of genetic and transcriptomic profiles in blood and underscore the potential utility of gene expression for risk prediction and deeper insight in molecular mechanisms underlying ADHD.

Are patients with bipolar disorder and comorbid attention-deficit hyperactivity disorder more neurocognitively impaired?

OBJECTIVE: Research on neurocognitive impairment in adult patients with comorbid bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) is very scarce. This study assessed the neurocognitive profile of a comorbid group (BD+ADHD) compared with that of pure BD (pBD) group, pure ADHD (pADHD) group and healthy controls (HCs). METHODS: This was a three-site study comprising 229 subjects: 70 patients with pBD, 23 with BD+ADHD, 50 with pADHD, and 86 HCs. All patients with BD had been euthymic for at least 6 months. Neuropsychological performance was assessed using a comprehensive neurocognitive battery. RESULTS: Our results showed that all the clinical groups had poorer performance than the HCs in all the neurocognitive domains except for executive functions. No significant differences were observed between the pBD and BD+ADHD groups in any of the cognitive domains, with these two groups showing greater impairment than the pADHD group in executive functions and visual memory. CONCLUSIONS: Our results, although preliminary, suggest that the BD+ADHD group showed the same neurocognitive profile as pBD patients, most likely reflecting the same neurobiological basis. On the other hand, the pADHD group showed a more selective moderate impairment in attention.

Dopamine receptor DRD4 gene and stressful life events in persistent attention deficit hyperactivity disorder.

We performed a case-control association study in persistent ADHD considering eight candidate genes (DRD4, DAT1/SLC6A3, COMT, ADRA2A, CES1, CYP2D6, LPHN3, and OPRM1) and found additional evidence for the involvement of the Dup 120bp and VNTR 48bp functional variants within the dopamine receptor DRD4 gene in the etiology of adult ADHD. We subsequently investigated the interaction of stressful life events with these two DRD4 polymorphisms, and the impact of such events on the severity of ADHD symptomatology. The gene-by-environment analysis revealed an independent effect of stressful experiences on the severity of persistent ADHD, and a gene-by-environment interaction on the inattentive dimension of the disorder, where non carriers of the Dup 120bp (L) - VNTR 48bp (7R) haplotype were more sensitive to environmental adversity than carriers. These results are in agreement with previous works reporting a relationship between DRD4 and the effect of adverse experiences, which may explain the discordant findings in previous genetic studies and strengthen the importance of gene-by-environment interactions on the severity of ADHD. © 2015 Wiley Periodicals, Inc.

Functioning Assessment Short Test (FAST): validity and reliability in adults with attention-deficit/hyperactivity disorder.

Studies highlight that the functional deficits in different areas of a subject's life are an important characteristic that define adult attention-deficit/hyperactivity disorder (ADHD). On the other hand, in the scientific literature, there are no evaluation instruments with psychometric studies concerning their reliability and validity for this variable in adults with ADHD. The aim of the present study is to evaluate the psychometric properties of the Functioning Assessment Short Test (FAST), regarding its reliability and validity, as a measure of adult ADHD functioning. A case-control study was carried out in a sample of 152 adult subjects (88 with ADHD diagnosis and 64 healthy controls). The psychometric properties of the instrument were analyzed regarding feasibility, internal consistency, concurrent validity, discriminant validity (ADHD vs. controls) and factor analysis. For the total scale, Cronbach's alpha was of 0.83, and strong values in the measures of its discriminant capacity were obtained, AUC ROC = 0.98, IC (0.96-0.99). The test is reliable as the internal consistency was high. Significant differences are observed in the correlation between domains, between healthy subjects and subjects with ADHD. ADHD subjects showed impairments in all areas of their life, especially in the cognitive functioning domain, followed by the autonomy, occupational functioning and interpersonal relationships domains. The FAST is an easily administered short interview and has good psychometric properties, in terms of reliability and validity, as a measure of the functional level in adults with ADHD. The study also showed that subjects with adult ADHD may be functionally impaired.

Emotional lability: the discriminative value in the diagnosis of attention deficit/hyperactivity disorder in adults.

OBJECTIVE: The aim of this study is to assess the discriminative value of emotional lability (EL) in the diagnosis of adults with ADHD. METHODS: A group of adults who met ADHD DSM-IV diagnostic criteria (n=589), a clinical control group (n=138) and a community control group (n=98) were compared in EL scores. SCID-I, SCID-II and CAADID were used to select subjects. The specific subscale on EL of the Conners Adult ADHD Rating Scale (CAARS) was used to evaluate EL. RESULTS: An analysis of the covariance was carried out in order to explore the association between EL, ADHD and comorbidity. The group factor (ADHD, clinical or community group) and the comorbidity factor (presence or absence of other psychiatric disorders different from ADHD) showed to be significant on EL intensity (group: F=81.78 p=0.000; comorbidity: F=25.48 p=0.000). However, no significant differences were found in the group × comorbidity interaction (F=1.006, p=0.366). EL showed a sensitivity of 87.1% and a specificity of 46.6% in discriminating between ADHD patients and subjects with other psychiatric disorders. CONCLUSION: EL is specifically related to ADHD and this association is not explained for the presence of other psychiatric disorders. The presence of comorbid disorders is only related to a major intensity of EL.

ADHD Rating Scale (ADHD-RS): Validation in Spanish in adult population according to the DSM-5.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is the most common childhood neurodevelopmental disorder, with an estimated prevalence in adulthood of 2.5-3.4%. The Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS) is an 18-item self-administered scale that assesses attention deficit and hyperactivity/impulsivity symptoms of ADHD in adults. This study aims to validate the ADHD-RS in Spanish according to the diagnostic criteria established by the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). MATERIALS AND METHODS: A sample of 441 adult patients (mean age 33.34±11.37 years) was included, 396 subjects were diagnosed with ADHD (mean age 33.17±11.18 years), and 45 were controls (mean age 35.40±12.33 years). The clinical diagnosis of ADHD was established according to the DSM-5 criteria. The ADHD-RS was subsequently administered to all participants. A logistic regression study evaluated the model in terms of sensitivity, specificity, positive predictive value, and negative predictive value. The Kaiser-Meyer-Olkin (KMO) measure was performed to assess the adequacy of the data set, and to determine whether factor analysis was applicable, Bartlett's sphericity test was performed. Principal component analysis was used, using the Varimax orthogonal rotation method, which minimizes the number of variables with high loads on each factor, obtaining two factors and thus, simplifying their interpretation. RESULTS: The cut-off point that best discriminates the combined presentation of ADHD was 24 points, with a sensitivity of 94.78%, a specificity of 84.79%, a PPV (positive predictive value) of 93.74%, and an NPV (negative predictive value) of 78.33, with an area under the curve (AUC) of 0.85, and a kappa coefficient of 0.86. Regarding inattentive ADHD, the cut-off point that best discriminates was 21 points, with a sensitivity of 92.56%, a specificity of 76.26%, a PPV of 92.01%, an NPV of 78.33%, an AUC of 0.90, and a kappa coefficient of 0.87. Different cut-off values in the two subgroups suggests that a differentiated cut-off point for the inattentive and combined presentations may be an adequate assessment strategy for ADHD in adulthood. CONCLUSIONS: The Spanish version of the ADHD-RS is a valid instrument to evaluate ADHD in adults according to the diagnostic criteria established by the DSM-5. Differentiated cut-off points for the inattentive and combined presentations discriminate more accurately than a single cut-off point.

The socioeconomic burden of adult attention-deficit/hyperactivity disorder in Spain.

Introduction: The symptoms of attention-deficit/hyperactivity disorder (ADHD) in adults highly interfere with function in multiple dimensions, increasing the economic burden associated with ADHD. The aim of this study was to explore the impact of ADHD in Spanish adults and estimate the associated economic burden within the healthcare, social, economic, and legal domains. Methods: An economic model was developed from a social perspective using a bottom-up approach, based on the scientific literature and a multidisciplinary expert group. Results: The cost incurred per diagnosed adult patient with ADHD included an annual cost of €15,652 and a one-time cost of €7,893 (3,035 M€ and 1,531 M€ for Spain, respectively). Regarding the annual cost, 50% was attributed to costs within the economic domain, of which 53% were work-absenteeism-related. Moreover, 28% was attributed to costs within the social domain, of which 74% were substance-abuse-related. Regarding the one-time cost, 52% was attributed to costs within the healthcare domain, of which approximately 50% were hospitalization-related costs. Moreover, 42% was attributed to costs within the legal domain, of which 62% were imprisonment-related costs. Conclusions: This is the first report on the socioeconomic burden of ADHD in Spanish adults, shedding light on the large burden that adult ADHD poses on the healthcare system and society at large, as symptoms have been shown to impact almost every aspect of life. This is particularly important for undiagnosed/untreated patients with ADHD in Spain, as appropriate treatments have shown positive results in these areas and may reduce its associated socioeconomic burden.

Psychoeducation for adults with attention deficit hyperactivity disorder vs. cognitive behavioral group therapy: a randomized controlled pilot study.

The aim of the present study was to assess the efficacy of psychoeducation as compared with cognitive behavioral group therapy in adults with attention deficit hyperactivity disorder (ADHD) who still had significant symptoms and were in pharmacological treatment. This is the first study on psychoeducation in adults with ADHD. Thirty-two individuals were randomized to two treatment conditions: 15 were in the psychoeducation group and 11 were in the cognitive behavioral group therapy. A total of 30 completed treatment, and 26 completed the follow-up assessments. The results indicated that both treatments were associated with statistically significant improvements on inattention, hyperactivity, impulsivity, and self-esteem. The patients in both groups showed a decrease in anxiety symptoms and obtained significantly lower scores in depression. Measures on functional impairment showed statistically significant differences on improved quality of life and on lower global severity as perceived in self-report and assessed by clinician report. Psychoeducation demonstrated to be an effective treatment in reducing ADHD core symptoms.

Comprehensive analysis of omics data identifies relevant gene networks for Attention-Deficit/Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that results from the interaction of both genetic and environmental risk factors. Genome-wide association studies have started to identify multiple genetic risk loci associated with ADHD, however, the exact causal genes and biological mechanisms remain largely unknown. We performed a multi-step analysis to identify and characterize modules of co-expressed genes associated with ADHD using data from peripheral blood mononuclear cells of 270 ADHD cases and 279 controls. We identified seven ADHD-associated modules of co-expressed genes, some of them enriched in both genetic and epigenetic signatures for ADHD and in biological pathways relevant for psychiatric disorders, such as the regulation of gene expression, epigenetics and immune system. In addition, for some of the modules, we found evidence of potential regulatory mechanisms, including microRNAs and common genetic variants. In conclusion, our results point to promising genes and pathways for ADHD, supporting the use of peripheral blood to assess gene expression signatures in psychiatric disorders. Furthermore, they highlight that the combination of multi-omics signals provides deeper and broader insights into the biological mechanisms underlying ADHD.

Insomnia Disorder in Adult Attention-Deficit/Hyperactivity Disorder Patients: Clinical, Comorbidity, and Treatment Correlates.

Introduction: Several investigations have been performed on insomnia symptoms in adult attention-deficit/hyperactivity disorder (ADHD). However, the relationship between insomnia disorder and adult ADHD has been neglected in research. The main objective of the current study is to analyze the differences between adult ADHD patients with and without insomnia disorder, in terms of ADHD clinical severity, medical and psychiatric comorbidity, psychopharmacological treatment, and quality of life. Material and Methods: Two hundred and fifty-two adult patients with ADHD (mean age 37.60 ± 13.22 years; ADHD presentations-combined: 56.7%, inattentive: 39.7%, hyperactive/impulsive: 3.6%) were evaluated with an exhaustive clinical and psychological evaluation protocol including semistructured interviews (for comorbidities and ADHD assessment) and symptom rating scales for ADHD. The diagnosis of ADHD and insomnia disorder was made according to DSM-5 criteria. Furthermore, the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale were administered. Results: Insomnia disorder was found in 44.4% of adult ADHD patients and was more common in combined presentation (64.3%) and in patients with more ADHD severity. Comorbidities (both medical and psychiatric), especially mood disorders (42%), anxiety disorder (26.8%), personality disorder (39.3%), and any substance use disorder (11.6%), were associated with a higher insomnia disorder prevalence. ADHD stimulant treatment was related to lower insomnia disorder compared to patients without medication, as well as ADHD stable treatment. Additionally, worse health-related quality of life was associated with insomnia disorder. Conclusion: Insomnia disorder is highly prevalent in adult ADHD and is related to higher ADHD severity and more psychiatric and medical comorbidities. Some stimulants and stable pharmacological ADHD treatment are associated with better outcomes of insomnia disorder.

Eye Vergence Responses During an Attention Task in Adults With ADHD and Clinical Controls.

Objective: ADHD patients show poor oculomotor control and recent studies show that attention-related eye vergence is weak in ADHD children. We aimed to assess vergence as a potential diagnostic biomarker for ADHD in adults. Method: We assessed the modulation in the angle of vergence while performing an attention task (N = 144), comparing the results for adults previously diagnosed with ADHD (N = 108) with age-matched clinical controls (N = 36). Results: Significant differences in eye vergence response modulation between clinical controls and ADHD patients were documented. Diagnostic test accuracy was 79%. Conclusion: In combination with an attention task, eye vergence responses could be used as an objective marker to support the clinical diagnosis of adult ADHD.

Transcriptome profiling in adult attention-deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with an estimated heritability of around 70%. Although the largest genome-wide association study (GWAS) meta-analysis on ADHD identified independent loci conferring risk to the disorder, the molecular mechanisms underlying the genetic basis of the disorder remain to be elucidated. To explore ADHD biology, we ran a two-step transcriptome profiling in peripheral blood mononuclear cells (PBMCs) of 143 ADHD subjects and 169 healthy controls. Through this exploratory study we found eight differentially expressed genes in ADHD. These results highlight promising candidate genes and gene pathways for ADHD and support the use of peripheral tissues to assess gene expression signatures for ADHD.

Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.

Functional impairment in adult bipolar disorder with ADHD.

BACKGROUND: It is well established that patients with either bipolar disorder (BD) or attention-deficit/hyperactivity disorder (ADHD) present functional impairment even when in remission. Nevertheless, research on functional impairment with adult patients with bipolar disorder comorbid to ADHD (BD+ADHD) is very scarce. The main objective of the current report was to evaluate the overall and specific domains of functioning, in patients with BD+ADHD compared to patients with pure bipolar disorder (pBD) and healthy controls (HCs). METHOD: 162 subjects from 3 groups were compared: 63 pBD, 23 BD+ADHD and 76 HCs. All the patients with BD had been euthymic for at least 6 months and they were recruited at the Hospital Clinic of Barcelona. All the participants were assessed with the 17-item Hamilton Depression Rating Scale (HAM-D), the Young Mania Rating Scale (YMRS) and the Functioning Assessment Short Test (FAST). Clinical, and sociodemographic data were also recorded. RESULTS: Clinical groups, pBD and BD+ADHD, showed lower overall functioning (p < 0.001) in each domain of the FAST scale compared to the HCs. Moreover, the Tukey post hoc test revealed that the BD+ADHD group showed a worse score than pBD in the cognitive domain of the FAST. However, after controlling for potential confounding variables, only the HDRS scores (p < 0.026) remained significant for the cognitive domain of the FAST. LIMITATIONS: The small sample size of the comorbid BD+ADHD group. CONCLUSIONS: Adult patients with BD+ADHD showed the worst scores in functioning compared with the HCs, but did not show more severe functional impairment than the pBD group except for the cognitive domain. Therefore our findings suggest that depressive symptoms in adults with BD+ADHD may negatively influence cognitive functioning. Further studies are needed to confirm our findings for the management of BD+ADHD.

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies.

Time and psychostimulants: Opposing long-term structural effects in the adult ADHD brain. A longitudinal MR study.

Long-term effects of psychostimulants such as methylphenidate on ADHD patients have been proved to be difficult to capture in cross-sectional studies comparing medicated and non-medicated samples and in longitudinal studies with children, with age-related maturational processes possibly confounding independent effects of medication. However, chronic psychostimulant administration at therapeutic doses has been proven to yield profound neuroadaptive changes in rodent models. Here, we present for the first time the effect of psychostimulant treatment on brain volumes in a sample of medication-naïve adult ADHD patients. We investigated grey matter volume changes in a sample of 41 medication-naïve adult ADHD patients before and after three years of psychostimulant treatment (N = 25) or no treatment (N = 16) compared to healthy adults (N = 25). We found a significant group x time interaction effect on left putamen grey matter volumes, with a decrease in left putamen volumes in the non-medicated group compared to both the medicated group and controls, and no differences between the medicated group and controls. Our results suggest a normalizing effect of psychostimulant treatment on the left putamen volume loss detected in non-medicated ADHD patients.

Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene-wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD.

[Cognitive-behavioural guidance interventions in adolescents with attention deficit hyperactivity disorder]. / Intervenciones de orientación cognitivo-conductual en adolescentes con trastorno por déficit de atención/hiperactividad.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that may become manifest at any time in life. In 50-70% of children diagnosed with the disorder it presents in adolescence. Young people with ADHD have high rates of comorbidity with other psychiatric disorders and a high degree of functional compromise. AIMS: To review the literature on cognitive-behavioural interventions that have been applied to the treatment of ADHD in adolescence. DEVELOPMENT: The studies that have been conducted on psychological treatment to date were reviewed, and the interventions were classified into: psychosocial treatments, mindfulness therapy and cognitive-behavioural treatment (individual and in groups). The only study on cognitive-behavioural therapy for adolescents with ADHD is also reviewed, as well as a new intervention protocol for application to groups designed at the Hospital Universitari Vall d'Hebron. CONCLUSIONS: Although there has been a recent increase in the number of publications dealing with the psychological treatment of ADHD in adolescents, there is a need for a greater development of intervention protocols and studies on their efficacy/effectiveness.

TITLE: Intervenciones de orientacion cognitivo-conductual en adolescentes con trastorno por deficit de atencion/hiperactividad.Introduccion. El trastorno por deficit de atencion/hiperactividad (TDAH) es un trastorno del neurodesarrollo que se puede manifestar a lo largo de la vida. Un 50-70% de los niños diagnosticados presenta el trastorno en la adolescencia. Los jovenes con TDAH tienen elevadas tasas de comorbilidad con otros trastornos psiquiatricos y una elevada afectacion funcional. Objetivo. Revisar la bibliografia de las intervenciones cognitivo-conductuales que se han aplicado al tratamiento del TDAH en la adolescencia. Desarrollo. Se revisan los estudios sobre tratamiento psicologico, clasificando las intervenciones en: tratamientos psicosociales, tratamiento en mindfulness y tratamiento cognitivo-conductual (individual y en formato de grupo). Se revisa el unico estudio publicado sobre terapia cognitivo-conductual para adolescentes con TDAH, asi como un nuevo protocolo de intervencion en formato de grupo diseñado en el Hospital Universitari Vall d'Hebron. Conclusiones. Aunque recientemente se ha incrementado el numero de publicaciones sobre el tratamiento psicologico del TDAH en el adolescente, se requiere un desarrollo mayor de protocolos de intervencion y estudios sobre la eficacia/efectividad de estos.

Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.

Genome-wide copy number variation analysis in adult attention-deficit and hyperactivity disorder.

Attention-deficit and hyperactivity disorder (ADHD) is a common psychiatric disorder with a worldwide prevalence of 5-6% in children and 4.4% in adults. Recently, copy number variations (CNVs) have been implicated in different neurodevelopmental disorders such as ADHD. Based on these previous reports that focused on pediatric cohorts, we hypothesize that structural variants may also contribute to adult ADHD and that such genomic variation may be enriched for CNVs previously identified in children with ADHD. To address this issue, we performed for the first time a whole-genome CNV study on 400 adults with ADHD and 526 screened controls. In agreement with recent reports in children with ADHD or in other psychiatric disorders, we identified a significant excess of insertions in ADHD patients compared to controls. The overall rate of CNVs >100 kb was 1.33 times higher in ADHD subjects than in controls (p = 2.4e-03), an observation mainly driven by a higher proportion of small events (from 100 kb to 500 kb; 1.35-fold; p = 1.3e-03). These differences remained significant when we considered CNVs that overlap genes or when structural variants spanning candidate genes for psychiatric disorders were evaluated, with duplications showing the greatest difference (1.41-fold, p = 0.024 and 2.85-fold, p = 8.5e-03, respectively). However, no significant enrichment was detected in our ADHD cohort for childhood ADHD-associated CNVs, CNVs previously identified in at least one ADHD patient or CNVs previously implicated in autism or schizophrenia. In conclusion, our study provides tentative evidence for a higher rate of CNVs in adults with ADHD compared to controls and contributes to the growing list of structural variants potentially involved in the etiology of the disease.