Raquel Vidal

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.

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.

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.

Prevalencia de síntomas de trastorno por déficit de atención con hiperactividad en adolescentes y adultos jóvenes con otros trastornos psiquiátricos refractarios a tratamientos previos

INTRODUCTION The aim of the current study was to assess the prevalence of symptoms of attention deficit/hyperactivity disorder (ADHD) in adolescents and young adults diagnosed with other primary psychiatric disorders, who had not responded to previous treatments. MATERIAL AND METHODS A total of 795 outpatients aged 15 to 24 years were included. The presence of ADHD was studied using DSM-IV criteria and the frequency of symptoms using the 18 item DuPaul ADHD Rating Scale. RESULTS ADHD (DSM-IV criteria) was present in 48 patients (6%), none of whom had previously received the diagnosis. A total of 260 patients (32.7%) met the criteria for moderate ADHD and between them, severity of primary psychiatric disorder was higher according to the CGI-S (P=.007). Risk factors for moderate ADHD symptoms were the presence of substance use disorders (SUD) (odds ratio=1.543, P=.01) and borderline personality disorders (odds ratio =2.173, p=.0001). CONCLUSION Unrecognized ADHD was present in 6% of patients; moreover 32.7% of the sample also presented moderate symptoms of the disorder. Screening for ADHD in young patients with refractory response to primary disorder treatment, mainly those with substance use disorders, conduct and personality disorders is highly advisable, due to the high frequency of ADHD comorbidity in these psychiatric disorders.

Toward a Better Understanding of Attention-Deficit/ Hyperactivity Disorder Across the Lifespan

T he article by Ramos et al. 1 published in this issue of the Journal provides a more comprehensive view of attention-deficit/hyperactivity disorder (ADHD) across the lifespan. In it, the authors address the relations between ADHD in childhood and risk taking, accidents, and medical illnesses in middle adulthood. The study also examines the role of co-occurring conduct disorder (CD) on risk taking during adulthood. Further, the article explores whether exposure to psychostimulants in childhood predicts cardiovascular disease later in life. Ramos et al. conducted a 33-year follow-up study of a large sample composed of 135 boys diagnosed with childhood ADHD but without CD. They matched probands with 136 male comparisons without a history of ADHD. Groups were assessed at a mean age of 41 years. The persistence of ADHD into adulthood has been well documented by genetic, neuroimaging, and longitudinal studies. ADHD in adults has been related to higher rates of comorbidity during childhood. However, previous longitudinal studies have rarely extended beyond early adulthood. This article has several important aspects of interest. It is among the first studies to prospectively examine the relation between ADHD and risk-taking behaviors, accidents, nonpsychiatric hospitalizations, and emergency department visits. It is the first study to follow the long-term health outcomes of children with ADHD over 30 years and well into the fourth and fifth decades of its subjects’ lives. The study is pioneering in examining the long-term effects of psychostimulants on cardiovascular health. The investigation suggests that the risky behaviors that continue into adulthood in individuals with childhood ADHD are largely accounted for by CD and antisocial personality disorder rather