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In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P

Background: Bipolar Disorder (BD) represents the seventh major cause of disability life-years-adjusted. Lithium remains as a first-line treatment, but clinical improvement occurs only in 30 % of treated patients. Studies suggest that genetics plays a major role in shaping the individual response of BD patients to lithium., Methods: We used machine-learning techniques (Advance Recursive Partitioned Analysis, ARPA) to build a personalized prediction framework of BD lithium response using biological, clinical, and demographical data. Using the Alda scale, we classified 172 BD I-II patients as responders or non-responders to lithium treatment. ARPA methods were used to build individual prediction frameworks and to define variable importance. Two predictive models were evaluated: 1) demographic and clinical data, and 2) demographic, clinical and ancestry data. Model performance was assessed using Receiver Operating Characteristic (ROC) curves., Results: The predictive model including ancestry yield the best performance (sensibility = 84.6 %, specificity = 93.8 % and AUC = 89.2 %) compared to the model without ancestry (sensibility = 50 %, Specificity = 94.5 %, and AUC = 72.2 %). This ancestry component best predicted lithium individual response. Clinical variables such as disease duration, the number of depressive episodes, the total number of affective episodes, and the number of manic episodes were also important predictors., Conclusion: Ancestry component is a major predictor and significantly improves the definition of individual Lithium response in BD patients. We provide classification trees with potential bench application in the clinical setting. While this prediction framework might be applied in specific populations, the used methodology might be of general use in precision and translational medicine., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has had negative effects on mental health. Understanding sex and age differences in the perception of stressors, the use of coping strategies, and the prevalence of depression and anxiety can lead to detecting at-risk groups., Methods: A cross-sectional online study surveyed perceived stressors, coping strategies, and the PHQ-9 and GAD-7 rating scales for symptoms of depression and anxiety. The study was open from Spring 2020 to Spring 2021 and was aimed at children, adolescents and young adults of Latin America., Results: The survey was completed by 3965 participants (63.8% females). The sample was divided into children (N = 621, 15.7%), adolescents (N = 1123, 28.3%) and young adults (N = 2021, 56%). Moderate to severe symptoms of depression and anxiety were found in 43.53% and 27%, respectively, being more frequent in females. Children of both sexes showed the lowest scores in rating scales. Adult females reported a higher level of stress in regards to pandemic news, having someone close diagnosed with COVID-19,the possibility of getting sick, academic delays, economic impact, and depression, while female adolescents reported a higher level of stress regarding the lockdown, losing contact with peers and anxiety. In juxtaposition, females also reported a higher frequency of positive coping strategies. A multivariate analysis confirmed the association of several variables with the presence of depression and anxiety., Conclusion: A high prevalence of depression and anxiety was found among young people. Specific intervention programs must be created taking into account age and sex differences., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Limited prosocial emotions (LPE) has been recently incorporated into international classifications as a specifier for conduct disorder in the DSM -5 and for all disruptive behavioural disorders in the ICD-11. The aims of the current work were to determine (a) the accuracy of each of the characteristics used to assess the LPE specifier and (b) whether the manner in which symptoms group together supports the idea of LPE having core characteristics., Method: Trained clinicians conducted interviews and determined LPE characteristics using responses from 74 parent/guardian and child/adolescent participants., Results: The distribution of LPE characteristics among those participants with LPE ( n = 13) was compared to those with only one LPE characteristic ( n = 11). The proposal of callous lack of empathy (CLE) and shallow deficient affect (SDA) as core characteristics was supported by strong associations with the presence of the LPE specifier, larger specificity, and sensitivity indices than those for unconcerned about performance and lack of remorse or guilt, as well as by a robust aggregation in a latent class analysis., Conclusions: CLE and SDA could be considered as core characteristics of LPE in children and adolescents.

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.

Background: Severe mental illness diagnoses have overlapping symptomatology and shared genetic risk, motivating cross-diagnostic investigations of disease-relevant quantitative measures. We analysed relationships between neurocognitive performance, symptom domains, and diagnoses in a large sample of people with severe mental illness not ascertained for a specific diagnosis (cases), and people without mental illness (controls) from a single, homogeneous population., Methods: In this case-control study, cases with severe mental illness were ascertained through electronic medical records at Clínica San Juan de Dios de Manizales (Manizales, Caldas, Colombia) and the Hospital Universitario San Vicente Fundación (Medellín, Antioquía, Colombia). Participants were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases had structured interview-based diagnoses of schizophrenia, bipolar 1, bipolar 2, or major depressive disorder. Linear mixed models, using CNB tests as repeated measures, modelled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses in cases included symptom factor scores obtained from exploratory factor analysis of symptom data as main effects., Findings: Between Oct 1, 2017, and Nov 1, 2019, 2406 participants (1689 cases [schizophrenia n=160; bipolar 1 disorder n=519; bipolar 2 disorder n=204; and major depressive disorder n=806] and 717 controls; mean age 39 years (SD 14); and 1533 female) were assessed. Participants with bipolar 1 disorder and schizophrenia had similar impairments in accuracy and speed across cognitive domains. Participants with bipolar 2 disorder and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, whereas high depression scores were associated with increased social cognition accuracy., Interpretation: Cross-diagnostic investigations showed that neurocognitive function in severe mental illness is characterised by two distinct profiles (bipolar 1 disorder and schizophrenia, and bipolar 2 disorder and major depressive disorder), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating severe mental illness causes and trajectories., Funding: US National Institute of Mental Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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.

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.

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., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Bipolar Disorder (BD) and schizophrenia are included in the group of severe mental illness and are main causes of disability and morbidity in the local population due to the bio-psycho-social implications in patients. In the last 20 years or so, adjunctive psychological interventions been studied with the purpose of decreasing recurrences, stabilising the course of the disease, and improving the functionality in these patients., Objective: To analyse the psychological effect of a multimodal intervention (MI) vs a traditional intervention (TI) program in BD I and schizophrenic patients., Methods: A prospective, longitudinal, therapeutic-comparative study was conducted with 302 patients (104 schizophrenic and 198 bipolar patients) who were randomly assigned to the MI or TI groups of a multimodal intervention program PRISMA. The MI group received care from psychiatry, general medicine, neuropsychology, family therapy, and occupational therapy. The TI group received care from psychiatry and general medicine. The Hamilton and Young scales, and the Scales for the Assessment of Negative Symptoms (SANS) and Postive Symptoms (SAPS) were used on bipolar and schizophrenic patients, respectively. The scales AQ-12, TEMPS-A, FAST, Zuckerman sensation seeking scale, BIS-11, SAI-E and EEAG were applied to measure the psychological variables. The scales were performed before and after the interventions. The psychotherapy used in this study was cognitive behavioural therapy., Results: There were statistically significant differences in socio-demographic and clinical variables in the schizophrenia and bipolar disorder group. There were no statistically significant differences in the psychological scales after conducting a multivariate analysis between the intervention groups and for both times (initial and final)., Conclusion: This study did not show any changes in variables of psychological functioning variables between bipolar and schizophrenic groups, who were subjected to TI vs MI (who received cognitive behavioural therapy). Further studies are needed with other psychological interventions or other psychometric scales., (Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Objective: Magnetic resonance imaging (MRI) studies in bipolar I disorder (BD-I) suggest that lithium is associated with increased volumes of cortico-limbic structures. However, more rigorous control of confounding factors is needed to obtain further support for this hypothesis. The aim of the present study was to assess differences in brain volumes among long-term lithium-treated BD-I patients, unmedicated BD-I patients, and healthy controls., Methods: This was a cross-sectional study with 32 euthymic BD-I patients (16 on lithium monotherapy for a mean of 180 months, and 16 receiving no medication for at least the 2 months prior to the study) and 20 healthy controls. Patients were euthymic (Hamilton Depression Rating Scale [HDRS] <6 and Young Mania Rating Scale [YMRS] <7) and had not taken psychotropic medications other than lithium for at least 6 months. Brain images were acquired on a 1.5 Tesla MRI (Phillips, Amsterdam, The Netherlands) and segmented to generate volumetric measures of cortical and subcortical brain areas, ventricles and global brain., Results: Significant differences were found in the volumes of the left amygdala (P=.0003), right amygdala (P=.030), left hippocampus (P=.022), left thalamus (P=.022), and right thalamus (P=.019) in long-term lithium-treated BD-I patients, compared to unmedicated patients and controls, after multivariable adjustment. No differences were observed in global brain volume or in ventricular size among the three groups. Likewise, there was no correlation between serum lithium levels and the increase in size in the described brain areas., Conclusions: The structural differences found among the three groups, and specifically those between long-term lithium-treated and unmedicated BD-I patients, indicate increased limbic structure volumes in lithium-treated patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Bipolar disorder and schizophrenia are causes of major suffering in patients. Nevertheless, they also affect family and caregiver functioning. This is important because the participation and involvement of families and caregivers is essential to achieve an optimal treatment., Objective: To describe the level of expressed emotions, burden, and family functioning of bipolar and schizophrenic patients and, to evaluate the efficacy of the multimodal intervention (MI) versus traditional intervention (TI) in family functioning and its perception by patients and caregivers., Material and Methods: A prospective, longitudinal, therapeutic-comparative study was conducted with 302 patients (104 schizophrenic and 198 bipolar patients) who were randomly assigned to a MI or TI groups of a multimodal intervention program PRISMA. MI group received care from psychiatry, general medicine, neuropsychology, family therapy, and occupational therapy. TI group received care from psychiatry and general medicine. Hamilton, Young and SANS, SAPS scales were applied to bipolar and schizophrenic patients, respectively. The EEAG, FEICS, FACES III and ECF were also applied at the initial and final time., Results: There were statistically significant differences in socio- demographic and clinical variables in schizophrenia vs bipolar group: 83% vs 32.2% were male, 37 vs 43 mean age, 96% vs 59% were single, 50% vs 20% unemployed, and 20% vs 40% had college studies. In addition, 2 vs 2.5 numbers of hospitalisations, 18 vs 16 mean age of substance abuse onset and, 55 vs 80 points in EEAG. There were no statistically significant differences in family scales after conducting a multivariate analysis on thr initial and final time in both groups., Conclusions: This study did not show changes in variables of burden and family functioning between bipolar and schizophrenic groups that were under TI vs MI., (Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

Background: Patients with bipolar disorder type I (BDI) have an increased prevalence of psychotic symptoms, and these have been associated with higher cognitive impairment; however the issue has not been settled with the available evidence., Objective: To determine if the history of psychotic symptoms in a Colombian sample with BDI is associated with greater cognitive impairment., Methods: A case-control study was performed that included patients with BDI from the l PRISMA study. Of the 203 eligible subjects, 123 participants were included; 71 had a history of psychosis, and 52 did not. Cognitive function was characterised by neuropsychological tests that assessed intellectual coefficient, attention, executive function, verbal fluency, auditory and visual memory, and spatial location., Results: No differences were found in most of the neuropsychological test results between the groups after adjusting for age, education, sex, duration of the disease, number of episodes, and use of benzodiazepines; however, there was differences in semantic FAS (P=.01), with a better performance in the group with a prior history of psychosis., Conclusions: The results suggest that there are no significant differences in the cognitive performance between patients with BDI in euthymic stage, with and without history of psychosis., (Copyright © 2016 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Introduction: Intermittent explosive disorder (IED) is aan externalizing externalising disorder characterized characterised by recurrent aggression episodes. Even though this disorder was described several decades ago, and it carries personal and social consequences, there is little in the medical scientific literature on this. bibliographic production about it is scanty., Objective: To perform a conceptualization conceptualisation of this disorder, through the review and bibliometric analysis of the available scientific articles., Material and Methods: A search was performed in databases with the english English terms intermittent explosive disorder, impulse disorders control [MeSH], in combination with other terms. A bibliometric analysis in the GoPubMed® search engineer was also performed using all data obtained in the search. was also perfomed., Discussion: IED prevalence ranges from 1.4% to 7%, it presents more frequently during middle adolescence, and with more noticeable repercussions in men males than in womenfemales. The psychopathological core of IED is the impulsive aggressive behaviour that presents in the form of «attacks» that occurs in response to a lower precipitating stimulus. Scientific publications about IED are few and relatively recent, and the vast majority is provided bycomes from the United States (56.56%), and headed by a single author. This fact highlights the need to replicate the findings described about the IED in order to demonstrate the validity and reliability of its diagnostic criteria. It is possible that doubts about the existence of a diagnosis lead have led to such a scant literature about the IED., Conclusions: Available studies about IED allow have allowed characterizing a group of subjects with episodes of impulsive aggression to be characterised, but this description requires replication in different latitudesneeds to be repeated in different areas., (Copyright © 2015 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Introduction: Inflammatory changes have been described in different affective episodes, as well as in the euthymic phase of Bipolar I Disease. These changes have been proposed as possible peripheral markers of the disease. For this reason well-designed studies are needed to explore this hypothesis., Objective: Quantify and compare the serum levels of interleukins (IL) and tumour necrosis factor (TNF) in bipolar I patients and healthy subjects, including the comparison between the affective episodes of the disease., Methods: Cross-sectional study including 41 bipolar I patients and 11 healthy control subjects. Serum levels of IL-1B, IL-RA, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, and TNF were measured during the euthymic, depressive, and manic phases and were compared with the serum levels of the healthy subjects., Conclusions: Manic phase patients had low education and high number of hospitalisations. Depressive phase patients showed high number of depressive episodes throughout life. No statistically significant differences were found in IL and TNF levels between bipolar I patients and healthy controls, or between the bipolar I subgroups (euthymic, manic and depressive states). An increase in the size of the sample is necessary in future studies, in order to enhance the statistical value of the results, and explore the inflammatory hypothesis of the bipolar disease., (Copyright © 2015 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood. Preliminary studies with proton magnetic resonance spectroscopy ((1)H-MRS) of the brain have reported differences in brain metabolite concentration-to-Cr ratios between individuals with ADHD and unaffected controls in several frontal brain regions including anterior cingulate cortex. Using multivoxel (1)H-MRS, we compared 14 individuals affected with ADHD to 20 individuals without ADHD from the same genetic isolate. After controlling by sex, age, and multiple testing, we found significant differences at the right posterior cingulate of the Glx/Cr ratio density distribution function between ADHD cases and controls (P < 0.05). Furthermore, we found several interactions of metabolite concentration-to-Cr ratio, age, and ADHD status: Ins/Cr and Glx/Cr ratios at the left posterior cingulate, and NAA/Cr at the splenius, right posterior cingulate, and at the left posterior cingulate. We also found a differential metabolite ratio interaction between ADHD cases and controls for Ins/Cr and NAA/Cr at the right striatum. These results show that: (1) NAA/Cr, Glx/Cr, and Ins/Cr ratios, as reported in other studies, exhibit significant differences between ADHD cases and controls; (2) differences of these metabolite ratios between ADHD cases and controls evolve in specific and recognizable patterns throughout age, a finding that replicates previous results obtained by structural MRI, where is demonstrated that brain ontogeny follows a different program in ADHD cases and controls; (3) Ins/Cr and NAA/Cr ratios, at the right striatum, interact in a differential way between ADHD cases and controls. As a whole, these results replicate previous 1H-MRS findings and add new intriguing differential metabolic and ontogeny patterns between ADHD cases and controls that warrant further pursue.

Introduction: Bipolar Disorder (BD) has a high heritability and is more prevalent in first-degree relatives with family history. This makes the bipolar offspring (BO) an ideal study group to evaluate the natural history and the prodromal symptoms of this disorder. The main psychopathological findings for this group in various studies are described in this review., Methods: Articles comparing the psychopathology of bipolar offspring to either the offspring of other psychiatric patients or the offspring of healthy controls were reviewed., Results: The reviewed studies showed that the BO group had higher rates of affective disorders when compared to the offspring of other psychiatric patients or the offspring of healthy controls. The high prevalence of anxiety disorders, ADHD, and disruptive behavior disorders in this population suggest that such disorders could be considered prodromes of mood disorders., Conclusions: The group of BO had a significantly higher risk of developing a wide range of psychiatric disorders besides BD. More longitudinal studies are needed to characterize this population at risk for BD and to elucidate the risk factors in the progression of this disorder., (Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association.

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

Common bean can be grown as a grain crop (dry beans) or as a fresh vegetable (snap beans/green beans), both items being important in nutritional terms for providing essential minerals and vitamins to the diet. Snap beans are thought to be derived predominantly from dry beans of the Andean genepool and to be of a recent European origin; however, the existence of Mesoamerican genepool characteristics especially in traditional indeterminate growth habit snap beans indicates a wider origin. The objective of this study was to evaluate genetic diversity within a set of 120 indeterminate (pole type) snap beans and 7 control genotypes representing each genepool using amplified fragment length polymorphism (AFLP) and simple sequence repeat or microsatellite (SSR) markers. The genotypes were predominantly from Asia, Europe and the United States but included some varieties from Latin America and Africa. AFLP polymorphism ranged from 53.2 to 67.7% while SSR polymorphism averaged 95.3% for the 32 fluorescent and 11 non-fluorescent markers evaluated and total expected heterozygosity was higher for SSR markers (0.521) than for AFLP markers (0.209). Both marker systems grouped the genotypes into two genepools with Andean and Mesoamerican controls, respectively, with the Mesoamerican group being predominant in terms of the number of genotypes assigned to this genepool. Phaseolin alleles were not tightly associated with genepool assignment indicating that introgression of this locus had occurred between the genepools, especially with phaseolin "S" in the Andean group (23.5%) and phaseolins "T" and "C" in the Mesoamerican group (12.2 and 8.2%, respectively). The implications of these results on the origin of pole type snap beans and on breeding strategies for this horticultural crop are discussed.

The neural nicotinic acetylcholine receptor α4 subunit (CHRNA4), at 20q13.2-q13.3, is an important candidate gene for conferring susceptibility to attention deficit/hyperactivity disorder (ADHD). Several studies have already looked for association/linkage between ADHD and CHRNA4 in different populations. We used the Pedigree Disequilibrium Test to search for evidence of association between ADHD and six SNP marker loci in families from the isolated Paisa population. We found that the T allele of SNP rs6090384 exhibits a deficit of transmission in unaffected individuals (OR = 5.43, IC 1.54-19.13) (global P value = 0.014). We also found significant association and linkage to extended haplotypes rs2273502-rs6090384 (combination of variants C-T, respectively) (P = 0.02) and rs6090384-rs6090387 (P = 0.04) (combination of variants T-G, respectively). SNP rs6090384, variant T, has also been reported to be associated with inattention in a previous study. This makes ours the ninth study to examine the association of CHRNA4 with ADHD and the seventh one to find evidence for association in a population with a different ethnicity.

Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes., (Copyright 2008 Wiley-Liss, Inc.)

Background: Attention-deficit/hyperactivity disorder (ADHD) comorbid with oppositional defiant disorder (ODD) or conduct disorder (CD) and substance abuse/dependence seems to represent a specific subset within the phenotypic ADHD spectrum., Methods: We applied complex segregation and linkage analyses in a set of multigenerational families densely segregating ADHD comorbid with ODD, CD, alcohol abuse/dependence, and nicotine dependence., Results: Our data suggest that ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD (logarithm of odds [LOD]=14.19), ADHD and CD (LOD=5.34), ODD and CD (LOD=6.68), and CD and alcohol abuse/dependence (LOD=3.98). In addition to previously reported ADHD susceptibility loci, we found evidence of linkage for comorbid ADHD phenotypes to loci at 8q24, 2p21-22.3, 5p13.1-p13.3, 12p11.23-13.3, 8q15, and 14q21.1-22.2. These results were replicated with an affected status phenotype derived from latent class clusters., Conclusions: Patterns of cosegregation of ADHD with comorbidities can inform our understanding of the inheritance patterns not only of ADHD but also of disruptive behavioral disorders and alcohol abuse/dependence. Refining the comorbid ADHD phenotype by determining the cosegregation profile of specific comorbidities might be a powerful tool for defining significant regions of linkage.

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.

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.

Association/linkage between dopamine D4 receptor (DRD4) polymorphisms and attention-deficit/hyperactivity disorder (ADHD) has been suggested by case-control- and nuclear-family-based studies. Here, we present a candidate gene analysis for DRD4 using 14 extended and multigenerational families segregating ADHD derived from the 'Paisa' community of Antioquia, Colombia, a genetic isolate. Two DRD4 polymorphisms (a 120 bp tandem duplication at the promoter and a 48 bp-VNTR at exon 3), reported associated to ADHD, were genotyped. Parametric and non-parametric linkage analyses, and a family-based association test (FBAT), the pedigree disequilibrium test (PDT), were applied to search for evidence of association/linkage. Two-point LOD scores were significantly negative, with values ranging from -3.21 (P=0.011158) to -7.66 (P=0.000091 at theta=0). Non-parametrical analysis resulted in nonsignificant evidence for linkage. The PDT showed a moderate trend toward significance of association/linkage between the 7-repeat (7R) allele at the 48 bp VNTR and ADHD (P=0.0578). Furthermore, the haplotype analysis shows a significant association/linkage of the 7R-240 bp haplotype (P=0.0467) with ADHD. Results suggest that either a moderate DRD4 genetic effect, or linkage disequilibrium of DRD4 with an ADHD disease locus in the vicinity or the linkage to a phenotypic component of the ADHD spectrum could be underlying this association/linkage. These results provide further evidence for the association of ADHD to genetic variation in or near to DRD4 and replicate the previously reported association between ADHD and the 7R allele.

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.

Introduction: Using a shortened rating scale, the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) has been reported to be very higher in a Colombian population. However, these data require clinical confirmation., Objective: To confirm clinically the prevalence of ADHD in Colombian children and adolescents., Patients and Methods: A randomized sample of 4 to 17 year old children and adolescents--184 males and 157 females--was selected from the schools. Sample was stratified in two socioeconomic status: high (4, 5, 6) and low (1, 2, 3). Several parents' and teachers' rating scales for the diagnosis of ADHD, standardized and validated in the Colombian population, were applied to the sample. The diagnosis of ADHD was confirmed using a semi-structured psychiatric and neurological interview, and medical histories revisions., Results: Analysis found that prevalence of ADHD is 17.1%. Distribution for ADHD types was: combined 9.4%, inattentive 6.7% and hyperactive-impulsive 1%. Prevalence for boys was significant higher (21.8%) than for girls (10.9%) (chi 2 = 11.8, p < 0.01). In male predominate combined type and in female inattentive. Higher prevalence was found in low socioeconomic strata. Preschool children have lower prevalence (6.2%) than school 6 to 11 year old children (22.6%) and adolescents (21.6%)., Conclusion: A higher prevalence of ADHD was confirmed in Colombian population.