Mutations in sphingolipid metabolism genes are associated with ADHD.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75-80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.

ADGRL3 (LPHN3) variants predict substance use disorder.

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.

Validity and reliability of the kiddie schedule for affective disorders and schizophrenia present and lifetime version DSM-5 (K-SADS-PL-5) Spanish version.

BACKGROUND: There are various language adaptations of the Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version (K-SADS-PL). In order to comply with the changes in DSM classification, the Spanish edition of the interview was in need of update and evaluation. METHODS: K-SADS-PL was adapted to correspond to DSM-5 categories. All clinicians received training, and a 90% agreement was reached. Patients and their parents or guardians were interviewed and videotaped, and the videos were exchanged between raters. Factor analysis was performed and inter-rater reliability was calculated only in the case of diagnoses in which there were more than five patients. RESULTS: A total of 74 subjects were included. The Factor Analysis yielded six factors (Depressive, Stress Hyperarousal, Disruptive Behavioral, Irritable Explosive, Obsessive Repetitive and Encopresis), representing 72% of the variance. Kappa values for inter-rater agreement were larger than 0.7 for over half of the disorders. CONCLUSIONS: The factor structure of diagnoses, made with the instrument was found to correspond to the DSM-5 disorder organization. The instrument showed good construct validity and inter-rater reliability, which makes it a useful tool for clinical research studies in children and adolescents.

Construct validity and parent-child agreement of the six new or modified disorders included in the Spanish version of the Kiddie Schedule for Affective Disorders and Schizophrenia present and Lifetime Version DSM-5 (K-SADS-PL-5).

Changes to the Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) incorporate the inclusion or modification of six disorders: Autism Spectrum Disorder, Social Anxiety Disorder, Intermittent Explosive Disorder, Disruptive Mood Dysregulation Disorder, Avoidant/Restrictive Food Intake Disorder and Binge Eating Disorder. The objectives of this study were to assess the construct validity and parent-child agreement of these six disorders in the Spanish language Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version (K-SADS-PL-5) in a clinical population of children and adolescents from Latin America. The Spanish version of the K-SADS-PL was modified to integrate changes made to the DSM-5. Clinicians received training in the K-SADS-PL-5 and 90% agreement between raters was obtained. A total of 80 patients were recruited in four different countries in Latin America. All items from each of the six disorders were included in a factor analysis. Parent-child agreement was calculated for every item of the six disorders, including the effect of sex and age. The factor analysis revealed 6 factors separately grouping the items defining each of the new or modified disorders, with Eigenvalues greater than 2. Very good parent-child agreements (r>0.8) were found for the large majority of the items (93%), even when considering the sex or age of the patient. This independent grouping of disorders suggests that the manner in which the disorders were included into the K-SADS-PL-5 reflects robustly the DSM-5 constructs and displayed a significant inter-informant reliability. These findings support the use of K-SADS-PL-5 as a clinical and research tool to evaluate these new or modified diagnoses.

Attention-deficit/hyperactivity disorder and comorbidities in 18 Paisa Colombian multigenerational families.

OBJECTIVE: Eighteen extended multigenerational families were recruited from the genetically isolated Paisa community in Colombia to conduct genetic studies of attention-deficit/hyperactivity disorder (ADHD). This report describes the inclusion strategy and clinical features of participants to facilitate comparisons with other data sets. METHOD: Families were selected through a fixed-sampling scheme beginning with child probands referred for clinical evaluation for ADHD. Direct structured psychiatric interviews were conducted with 433 informative individuals, including 92 children aged 4 to 11, 57 adolescents aged 12 to 17, and 284 adults. Best estimate ADHD diagnoses were established for each informative pedigree member. RESULTS: These families contained a high proportion of individuals affected with ADHD (32.8%), which was highly comorbid with conduct disorder (50%; odds ratio 11.5, 95% confidence interval = 6.4-20.9), oppositional defiant disorder (25.4%; odds ratio 2.7, confidence interval = 1.5-4.8), and associated conditions including nicotine dependence and alcohol abuse and/or dependence. CONCLUSIONS: ADHD in these extended Paisa families is highly comorbid with conduct and oppositional defiant disorders. This pattern of comorbidity, as well as the large dense pedigrees of the sample, suggests that it will be particularly useful for molecular genetic studies that are currently under way.

Prevalence estimations of attention-deficit/hyperactivity disorder: differential diagnoses and comorbidities in a Colombian sample.

The aim of this article was to analyze the prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) in Colombian "Paisa" children and adolescents. A randomized sample of 4- to 17-year-old children and adolescents--176 males and 154 females--was selected from schools in Manizales, Colombia. The diagnosis of ADHD was obtained using a semistructured psychiatric and neurological interview, medical histories revision, and neurological or psychiatric evaluations. Several rating scales and a neuropsychological assessment were administered in order to confirm the diagnosis. Children with Full Scale Intelligence Quotient (FSIQ) between 71 and 84 were recorded as having Borderline Intellectual Functioning (BIF), and those with a history of mild motor retardation, and/or Performance Intelligence Quotient (PIQ) lower than 71, were recorded as having a Developmental Coordination disorder (DCD), after confirmation by neurological and neuropsychological examinations. BIF and DCD children were excluded from the ADHD group. Total prevalence of ADHD adjusted by sex was 16.4% (males 19.8% and females 12.3%). Prevalence of clean ADHD cases was 11.5%, distributed as follows: combined type, 6.4%; inattentive, 4.8%; and hyperactive-impulsive, 0.3%. Distribution by sex was as follows: males, 14.8%; and females, 7.7%; with an odds ratio of 2.1 (95% CI: 1-4.5, chi 2 = 4.0, p < .05). Clean prevalence of ADHD adjusted by equal sex distribution was 11.3%. Prevalence of BIF was 5.8%, DCD 3.0%, and mild mental retardation 3.9%. Prevalence of ADHD did not show differences by socioeconomic status (SES), in contrast to mild mental retardation in which BIF and DCD were significantly more frequent in the lower SES.

Trastorno por déficit de atención en una comunidad paisa: informe preliminar / Prevalence of attention deficit hyperactivity disorder in a paisa community: preliminary report

La prevalencia del trastorno por déficit de atención, cuando se utilizan instrumentos de diagnóstico epidemiológico y de aplicación a padres de niños paìsas, puede llegar al 16.1-18/100; estas cifras han sido criticadas por apoyarse en una sola fuente de información. El objetivo del estudio fue establecer la prevalencia del trastorno en una comunidad paisa usando multiples métodos para su diagnóstico. Se seleccionó de manera aleatoria una muestra de 341 niños y adolescentes de 4 a 17 años, 184 niños y 157 niñas de los colegios de la ciudad de Manizales. Se estratificaron en dos niveles socioeconómicos. Para el diagnóstico se utilizaron diversos cuestionarios, destinados a padres y maestros para la evaluación de la conducta de los niños y los adolescentes, previamente estandarizados en la población paisa. El diagnóstico se confirmó mediante una entrevista neurológica y psiquiátrica semiestructurada, se revisaron las historicas clínicas y se hizo una evaluación clínica neurológica y psiquiátrica cuando fue necesario. El análisis preliminar de los datos obtenidos, muestra que la prevalencia de la enfermedad y de acuerdo a los criterios de DSM IV, fue del 17.1/100. La distribución según tipos fue: combinado, inatento e hiperactivo-impulsivo. La prevalencia de la enfermedad en la comunidad paisa, según estos estudios es más alta que la informada en estudios de otras poblaciones