Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility.

The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = -2.701; p = 0.0069); rs1947274 A allele (Z score = -2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = -0.822; p = 0.4109); and rs2345039 C allele (Z score = -1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3's role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD.

Exocytosis-related genes and response to methylphenidate treatment in adults with ADHD.

Experimental studies have demonstrated that methylphenidate (MPH) modulates the synaptic vesicle trafficking and synaptotagmin-1 (SytI) mRNA levels. SytI is a regulatory protein of the SNARE complex, a neurotransmitter exocytosis mediator. Despite this evidence, most SNARE complex-related genes have never been evaluated in attention-deficit/hyperactivity disorder (ADHD) pharmacogenetics. This study evaluates, for we believe the first time, polymorphisms on the SNARE complex-related genes STX1A (rs2228607), VAMP2 (26bp Ins/Del) and SYT1 (rs1880867 and rs2251214) on the response to immediate-release methylphenidate (IR-MPH) in a naturalistic sample of adults with ADHD. The sample comprised 433 subjects, of which 272 (62.8%) have completed the short-term IR-MPH treatment (at least 30 days). The main outcome measure was the categorical variable of short-term response to IR-MPH based on the Swanson, Nolan and Pelham Rating Scale version 4 (SNAP-IV), and on the clinical global impression-improvement scale. Additional analyses evaluated the percentage of SNAP-IV symptom reduction for each dimension as well as short- and long- (7 years) term treatment persistence. SYT1-rs2251214 was associated with the categorical short-term response to IR-MPH (P=0.006, PFDR=0.028), and with the percentage of inattention and oppositional defiant disorder symptoms reduction (P=0.007, PFDR=0.028 and P=0.017, PFDR=0.048, respectively). SYT1-rs2251214 was also associated with short-term treatment persistence (P=0.018, PFDR=0.048), and with months of treatment (P=0.002, PFDR=0.016) in the long-term protocol. Our findings suggest that SYT1-rs2251214 presents a broad influence in IR-MPH response variability in adults with ADHD, being involved with both symptom response and treatment persistence. If such findings are replicated, SytI could represent a key element in MPH pharmacodynamics in adults with ADHD.

Trajectories of attention-deficit/hyperactivity disorder dimensions in adults.

OBJECTIVE: There is a lack of available information on the trajectories of attention-deficit/hyperactivity disorder (ADHD) dimensions during adulthood. This study investigates the course and the predictors of change for each ADHD domain in a clinical sample of adults with ADHD. METHOD: Adults with ADHD (n = 344) were followed up for 7 years, with a final retention rate of 66.0%. Trajectories of inattention, hyperactivity, and impulsivity and their potential predictors were examined. RESULTS: On average, symptoms declined in all ADHD domains during follow-up. Despite this, rises in inattentive, hyperactive, and impulsive symptoms were observed in approximately 13%, 25%, and 17% of patients respectively. Different predictors influenced the trajectory of each ADHD dimension. Oppositional defiant disorder and social phobia were associated with the maintenance of symptoms, while alcohol use disorder was associated with both maintenance and rise of symptoms. CONCLUSION: Unexpectedly, a rise in the symptoms after 7 years was not uncommon in adults with ADHD. Prevalent comorbidities have the potential to influence the neurodevelopment and the trajectory of ADHD. Therefore, such predictors should be investigated in population cohorts to better characterize the course of ADHD. Additionally, these findings may be relevant in prevention studies and in strategies for ADHD treatment.

Exome chip analyses in adult attention deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E-06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E-08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E-07); the PSD locus (P=7.58E-08) and ZCCHC4 locus (P=1.79E-06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E-05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD.

Persistence and remission of ADHD during adulthood: a 7-year clinical follow-up study.

BACKGROUND: Course and predictors of persistence of attention deficit hyperactivity disorder (ADHD) in adults are still largely unknown. Neurobiological and clinical differences between child and adult ADHD raise the need for follow-up studies of patients diagnosed during adulthood. This study investigates predictors of ADHD persistence and the possibility of full remission 7 years after baseline assessment. METHOD: A 7-year follow-up study of adults with ADHD (n = 344, mean age 34.1 years, 49.9% males) was conducted. Variables from different domains (social demographics, co-morbidities, temperament, medication status, ADHD measures) were explored with the aim of finding potential predictors of ADHD persistence. RESULTS: Retention rate was 66% (n = 227). Approximately a third of the sample (n = 70, 30.2%) did not maintain ADHD criteria and 28 (12.4%) presented full remission (<4 symptoms), independently of changes in co-morbidity or cognitive demand profiles. Baseline predictors of diagnostic persistence were higher number of inattention symptoms [odds ratio (OR) 8.05, 95% confidence interval (CI) 2.54-25.45, p < 0.001], number of hyperactivity/impulsivity symptoms (OR 1.18, 95% CI 1.04-1.34, p = 0.01), oppositional defiant disorder (OR 3.12, 95% CI 1.20-8.11, p = 0.02), and social phobia (OR 3.59, 95% CI 1.12-11.47, p = 0.03). CONCLUSIONS: Despite the stage of brain maturation in adults suggests stability, approximately one third of the sample did not keep full DSM-IV diagnosis at follow-up, regardless if at early, middle or older adulthood. Although full remission is less common than in childhood, it should be considered as a possible outcome among adults.

Harrow: new Drosophila hAT transposons involved in horizontal transfer.

In this study we characterize the transposable elements harrow, which belong to the hAT superfamily of DNA transposons. Searches for harrow sequences were performed in 65 Drosophilidae species, mainly representing Neotropical and cosmopolitan groups from the genus Drosophila. The nucleotide divergence among elements found in these species suggests that harrow sequences could be clustered in a subfamily. The patchy distribution throughout the genus Drosophila and the high similarity presented between all harrow sequences indicate that horizontal transfer could play a major role in the evolution of harrow elements. The results obtained suggest an evolutionary scenario in which harrow would have undergone multiple horizontal transfer events in the Neotropics, involving D. tripuncatata, D. mojavensis (Subgenus Drosophila) and several species of the willistoni and saltans groups (subgenus Sophophora).