Montse Corrales

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.

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

Abstract 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.

Validez de criterio y concurrente de la versión española de la Conners Adult ADHD Diagnostic Interview for DSM-IV

INTRODUCTION Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in adulthood. Its diagnosis requires a retrospective evaluation of ADHD symptoms in childhood, the continuity of these symptoms in adulthood, and a differential diagnosis. For these reasons, diagnosis of ADHD in adults is a complex process which needs effective diagnostic tools. AIM To analyse the criterion validity of the CAADID semi-structured interview, Spanish version, and the concurrent validity compared with other ADHD severity scales. METHODS An observational case-control study was conducted on 691 patients with ADHD. They were out-patients treated in a program for adults with ADHD in a hospital. RESULTS A sensitivity of 98.86%, specificity 67.68%, positive predictive value 90.77% and a negative predictive value 94.87% were observed. Diagnostic precision was 91.46%. The kappa index concordance between the clinical diagnostic interview and the CAADID was 0.88. Good concurrent validity was obtained, the CAADID correlated significantly with WURS scale (r=0.522, P<.01), ADHD Rating Scale (r=0.670, P<.0.1) and CAARS (self-rating version; r=0.656, P<.01 and observer-report r=0.514, P<.01). CONCLUSION CAADID is a valid and useful tool for the diagnosis of ADHD in adults for clinical, as well as for research purposes.

Personality profile of adult ADHD: the alternative five factor model.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most frequently diagnosed disorders in childhood affecting around 3% to 5% of adults worldwide. Most of the studies have been carried out using the Five Factor Model (FFM). Given the value and importance of describing adult ADHD in terms of general personality structure for a better conceptualization of this disorder, this study contributes adding new data on an Alternative Five Factor Model (AFFM) of personality. The aim of the present study is twofold: To assess the personality profile of adults with ADHD under the AFFM perspective, and to test the discriminant validity of the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) in differentiating ADHD subjects vs. normal range controls. A sample of 217 adults (64% male) meeting ADHD diagnosis (DSM-IV) was paired by age and sex with 434 normal-range controls. Logistic regression analysis showed that high scores on Neuroticism-Anxiety, Impulsivity and General Activity, and low on Work Activity were the most powerful predictors of being endorsed with an ADHD diagnosis. Results may suggest refinements in the personality assessment of ADHD as it seems that the ZKPQ provides more specific subscales for the description and conceptualization of this disorder.

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.

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.

Preliminary evidence for association of genetic variants in pri-miR-34b/c and abnormal miR-34c expression with attention deficit and hyperactivity disorder

Attention deficit and hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by impairment to sustain attention and inability to control impulses and activity level. The etiology of ADHD is complex, with an estimated heritability of 70–80%. Under the hypothesis that alterations in the processing or target binding of microRNAs (miRNAs) may result in functional alterations predisposing to ADHD, we explored whether common polymorphisms potentially affecting miRNA-mediated regulation are involved in this psychiatric disorder. We performed a comprehensive association study focused on 134 miRNAs in 754 ADHD subjects and 766 controls and found association between the miR-34b/c locus and ADHD. Subsequently, we provided preliminary evidence for overexpression of the miR-34c-3p mature form in peripheral blood mononuclear cells of ADHD subjects. Next, we tested the effect on gene expression of single-nucleotide polymorphisms within the ADHD-associated region and found that rs4938923 in the promoter of the pri-miR-34b/c tags cis expression quantitative trait loci for both miR-34b and miR-34c and has an impact on the expression levels of 681 transcripts in trans, including genes previously associated with ADHD. This gene set was enriched for miR-34b/c binding sites, functional categories related to the central nervous system, such as axon guidance or neuron differentiation, and serotonin biosynthesis and signaling canonical pathways. Our results provide preliminary evidence for the contribution to ADHD of a functional variant in the pri-miR-34b/c promoter, possibly through dysregulation of the expression of mature forms of miR-34b and miR-34c and some target genes. These data highlight the importance of abnormal miRNA function as a potential epigenetic mechanism contributing to ADHD.

An association study of sequence variants in the forkhead box P2 (FOXP2) gene and adulthood attention-deficit/hyperactivity disorder in two European samples.

Objectives Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder manifesting as symptoms of inattention, hyperactivity, and/or impulsivity. Learning disabilities co-occur with ADHD in 20–30% of cases and this high co-occurrence raises the possibility of a common etiological background. Forkhead box P2 (FOXP2) encodes a transcription factor involved in speech and language impairment and in the control of the corticobasal ganglia circuits known to be relevant in ADHD, suggesting a possible role of FOXP2 in ADHD. Our aim was to carry out an association study between FOXP2 and adulthood ADHD. Methods We carried out a case–control association study in 643 adult ADHD patients and 619 controls from Germany and in 361 adult ADHD patients and 442 controls from Spain with 12 tagging single nucleotide polymorphisms covering the FOXP2 gene. Results The single-marker and multiple-marker analyses showed an association between FOXP2 and combined ADHD in the German cohort [rs12533005: P=0.0033; odds ratio=1.30 (1.09–1.56); rs12533005/rs1229761: P=4.1e−04; odds ratio=1.38 (1.15–1.66)]. These positive results, however, were not confirmed in the Spanish sample. Conclusion Although these preliminary findings provide a tentative evidence for the contribution of FOXP2 to ADHD and suggest common genetic factors for this psychiatric disorder and learning disabilities, they should be interpreted with caution. Further studies in larger samples are needed to clarify the role of this transcription factor in ADHD.

Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder.

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder. However, a considerable interindividual variability exists in clinical outcome, which may reflect underlying genetic influences. We analyzed 57 single-nucleotide polymorphisms in 9 dopamine-related candidate genes (TH, DBH, COMT, DAT1 and DRD1-5) as potential predictors of MPH efficacy and tolerability, and we considered prenatal and perinatal risk factors as environmental hazards that may influence treatment effects in a gene-by-environment analysis. Our results provide evidence for the contribution of DRD3 (P=0.041; odds ratio (OR)=4.00), DBH (P=0.032; OR=2.85), TH (P=5.5e-03; OR=4.34) and prenatal smoking (P=1.7e-03; OR=5.10) to the clinical efficacy of MPH, with a higher risk for treatment failure in genetically susceptible subjects whose mother smoked during pregnancy. Adverse events after MPH treatment were significantly associated with variation in DBH (P=6.4e-03; OR=0.28) and DRD2 (P=0.047; OR=3.76). This study suggests that the dopaminergic system together with prenatal smoking exposure may moderate MPH treatment effects.

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.