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Abstract

Segregation analyses converge in explaining the predisposition to attention-deficit/hyperactivity disorder (ADHD) as the consequence of a major gene and exclude purely environmental or cultural transmission. As a result of the ADHD phenotype restrictions, collection of extended families or design of linkage studies using families has been extremely difficult and thus currently linkage studies have been performed using only concordant or discordant sib-pairs rather than large families. On the other hand, intergenerational studies are represented by the transmission disequilibrium test (TDT) using trios. We collected pedigree data on ADHD from the Paisa community from Antioquia, Colombia, a genetic isolate. The goal of this study was to genetically map a putative gene predisposing to ADHD in a set of 27 multigenerational Paisa families. Here we present the results of a power simulation using SIMLINK to detect linkage of ADHD. ADHD was assumed to be a dichotomous trait with incomplete penetrance and a phenocopy rate of 3% in males and 0.2% in females. We simulated cosegregation of the trait and a marker locus in our pedigrees. We assumed Hardy-Weinberg and linkage equilibrium, equally frequent marker alleles and evaluated power at several recombination fractions between the trait and marker loci. Also, the ADHD trait was assumed to be genetically heterogeneous and different functions of age-dependent penetrance were simulated. We found exceptionally good power to detect linkage (expected LOD > 14 if theta is 0.1 or less), and that the presence of heterogeneity up to 50% does not affect substantially the projected LOD scores even for a theta recombination value of 0.05 (eLOD > 5.87). Having now obtained blood samples and confirmatory interviews in five families (representing 20% of the projected number of families), we performed a new analysis. The expected mean LOD in these five families reached values close to 10 and remained invariant when heterogeneity and different penetrance models were considered. We discuss the relative benefits of using extended and multigenerational families for genetic mapping studies as opposed to using nuclear families, affected sib pairs or sporadic cases which require the collection of over 1000 analytical units to get the same power exhibited by the small number of pedigrees described here.

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... Family ascertainment and sample size has been described in our previous studies. 5,6 Briefly, Paisa descent was considered as having all four grandparents originating from the Paisa region of Colombia. The original sample consisted of 1077 family members, 725 (67.3%) adults (17 years and older) and 352 (32.7%) children and adolescents (6-16 years old), from 141 nuclear and multigenerational families (126 nuclear and 15 extended and multigenerational families) from the Paisa genetic isolate [5][6][7][8] with an average family size of 38.5 (range 5-85 individuals) and an average of 3.62 generations (range 2-5). ...
... 5,6 Briefly, Paisa descent was considered as having all four grandparents originating from the Paisa region of Colombia. The original sample consisted of 1077 family members, 725 (67.3%) adults (17 years and older) and 352 (32.7%) children and adolescents (6-16 years old), from 141 nuclear and multigenerational families (126 nuclear and 15 extended and multigenerational families) from the Paisa genetic isolate [5][6][7][8] with an average family size of 38.5 (range 5-85 individuals) and an average of 3.62 generations (range 2-5). Upon obtaining written informed consent from participating subjects and/or their parents/legal guardians, pedigrees were built through a fixed sampling scheme from a parent or grandparent of an index proband as approved by the University of Antioquia Ethics Committee (Protocol: 11-13-342). ...
... Full details of the clinical, demographic and genetic ascertainment features, as well as the methodology of endophenotype characterization were published elsewhere. [5][6][7][8] Whole-genome scan non-parametric linkage Genotyping of microsatellite markers was previously described. 7 A total of 372 markers across the whole genome, with an average distance of 8.68 cM, were genotyped in the aforementioned study (Table 1). ...
Article
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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.
... 39 Since the TDT detects the simultaneous presence of linkage and linkage disequilibrium (it cannot detect either in the absence of the other), the involvement of DRD4 by itself or the presence of another locus or loci in the neighborhood has been strongly suggested. 8,40 Under the premise that a major gene is underlying the susceptibility to ADHD, we explored this association/linkage between DRD4 polymorphisms and ADHD using 14 extended, multigenerational families from the 'Paisa' community of Antioquia, a genetic isolate located in Colombia, segregating the ADHD phenotype under a dominant model and exhibiting significant power to detect both linkage 41 and association/linkage with FBATs. ...
... A more detailed description of the Paisas has been published elsewhere. [41][42][43][44][45] Racial admixture estimations, 43 evolutionary reconstruction using phylogenetic methods, 44,46 genotyping of specific chromosomal Y and mitochondrial markers 46 and the presence of strong founder effects for some deleterious mutations resulting in neurodegenerative diseases, such as Early Onset Alzheimer Disease (PS-1 E280A), CADASIL (notch3 C455R) and Parkinson Disease (Parkin Cys212Tyr), [47][48][49][50][51][52] all support the conclusion that this community exhibits the features of a genetic isolate. ...
... From the pen2 model, we derived penetrance model 2b (pen2b) that assumes penetrance is 0 at age 0 and reaches its maximum at 10 years of age, and penetrance model 2c (pen2c) in which the penetrance is 0 for ages 0-4 years and reaches its maximum at 10 years of age. 41 Furthermore, we analyzed changes in the non-carriers' penetrance permitting a rate of phenocopies reaching 17% (maximum prevalence for ADHD estimated in the Paisa population. 70,71 Maximum LOD scores, after considering the presence of heterogeneity, were estimated using the HOMOG suite of programs implemented in ANALYSIS. ...
Article
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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.
... Strong evidence from family, twin, and genome-wide linkage and association studies suggests that genetic factors play a crucial role in shaping the susceptibility to both ADHD and SUD [18][19][20][21] . During the last 15 years, we have collected families clustering individuals affected with ADHD and disruptive behaviors from disparate regions around the world 6,18,22,23 . Although the prevalence of ADHD co-morbid with disruptive behaviors is variable across populations, we found a higher frequency of CD, ODD, and SUD (mainly nicotine dependence and alcohol abuse) in ADHD individuals than in unaffected relatives 6,22,24 . ...
... This population isolate is unique in that it was used to identify ADHD susceptibility genes by linkage and association strategies. Detailed clinical and demographic information on this sample has been published elsewhere 23,25,29 . The sample consists of 1176 people (adults, adolescents, and children), mean age 28 ± 17 years, ascertained from 18 extended multigenerational and 136 nuclear Paisa families inhabiting the Medellin metropolitan area in the State of Antioquia, Colombia. ...
Article
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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.
... Culturally, people behave as a typical Caribbean community, which have been constituted by periodic waves of internal and external immigrants (Villalón 2008). This community has predominantly mix ethnicity (racial intermix between white European [Andalusian-Spanish], black African, Syrian-Lebanese [Arabian], Jewish, and Amerindian people) (Barragán-Duarte 2007), which differs from the Colombian Andean ''paisa'' community previously described as a genetic isolate with a high prevalence (11-15%) of ADHD (Arcos-Burgos et al. 2002, 2004. ...
... A previously used (Arcos-Burgos et al. 2002;Palacio et al. 2004;Jain et al. 2006) structured neurologic interview was utilized to ascertain ADHD gold standard diagnosis, which need to exclude any major neurologic disease that could better explain the symptoms (DSM-V ADHD criterion E). This interview was administered to both parents in one session of 15 min. ...
Article
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Impairment in inhibitory control has been postulated as an underlying hallmark of attention deficit/hyperactivity disorder (ADHD), which can be utilized as a quantitative trait for genetic studies. Here, we evaluate whether inhibitory control, measured by simple automatized prepotent response (PR) inhibition variables, is a robust discriminant function for the diagnosis of ADHD in children and can be used as an endophenotype for future genetic studies. One hundred fifty-two school children (30.9% female, 67.8% with ADHD) were recruited. The ADHD checklist was used as the screening tool, whilst the DSM-IV Mini International Neuropsychiatry Interview, neurologic interview and neurologic examination, and the WISC III FSIQ test were administered as the gold standard procedure to assert ADHD diagnosis. A Go/No-Go task using a naturalistic and automatized visual signal was administered. A linear multifactor model (MANOVA) was fitted to compare groups including ADHD status, age, and gender as multiple independent factors. Linear discriminant analysis and the receiver operating characteristic curve were used to assess the predictive performance of PR inhibition variables for ADHD diagnosis. We found that four variables of prepotent response reaction time- and prepotent response inhibition established statistically significant differences between children with and without ADHD. Furthermore, these variables generated a strong discriminant function with a total classification capability of 73, 84% specificity, 68% sensitivity, and 90% positive predictive value for ADHD diagnosis, which support reaction times as a candidate endophenotype that could potentially be used in future ADHD genetic research.
... Based on simulations, we found that these extended families provide extraordinarily high estimates of statistical power for locating major susceptibility genes. 12 Simulations of statistical power in these large, multigenerational, densely affected families have also demonstrated exceptionally good power to detect linkage with expected LOD (logarithm of the odds) scores Ͼ 14 for recombination fractions of 0.1 or less, and expected LOD scores Ͼ 5.87 even if genetic heterogeneity were present in 50% of the families. 12 Thus, based on both the psychiatric characteristics of the participants, as well as structural genetic factors, we believe that these families will be highly informative regarding major susceptibility genes for ADHD, possibly in association with conduct disorder. ...
... 12 Simulations of statistical power in these large, multigenerational, densely affected families have also demonstrated exceptionally good power to detect linkage with expected LOD (logarithm of the odds) scores Ͼ 14 for recombination fractions of 0.1 or less, and expected LOD scores Ͼ 5.87 even if genetic heterogeneity were present in 50% of the families. 12 Thus, based on both the psychiatric characteristics of the participants, as well as structural genetic factors, we believe that these families will be highly informative regarding major susceptibility genes for ADHD, possibly in association with conduct disorder. We predict that studying a combination of sibpairs, cases and controls, in addition to extended, multigenerational families from a genetic isolate, will be most successful in eventually identifying ADHD susceptibility genes: advantages (in green) and disadvantages (in red) of these different approaches are shown in Figure 1. ...
Article
Complex genetic traits refer to those phenotypes not fitting patterns of Mendelian segregation and/or assortment but exhibiting a preferential familial clustering that cannot be explained by cultural or environmental causes. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder of childhood and probably the most controversial. ADHD has been considered a complex genetic trait based upon the absence of a clear-cut boundary between affected and unaffected status. Furthermore, its high comorbidity with other disorders strongly suggests complex epistatic or pleiotropic effects acting in common with the environmental influences. This implies that the same gene or genes is or are associated with different and concurrently occurring phenotypes. In this study, we will review clinical and epidemiological aspects related to the ADHD phenotype, which are considered either as categorical or continuous traits. We also will discuss genetic models underlying the complexity of this behavioral phenotype and the probable role of epistatic interactions between major genes contributing to the ADHD phenotype.
... El objetivo de esta investigación es determinar en una familia multigeneracional extendida perteneciente a la comunidad Paisa de Antioquia, una población aislada genéticamente localizada en Colombia [12,13], que segrega para EIG y con un fuerte poder para detectar ligamiento, si existe susceptibilidad para desarrollar EIG en las regiones q22 -q24 del cromosoma 8, p13.3 del cromosoma 16 y q22.3 del cromosoma 21. ...
... Tras la obtención del consentimiento informado por escrito de cada miembro de la familia Epi1 perteneciente a la comunidad Paisa, ya descrita [12,13,15,16], y con un efecto fundador para algunas mutaciones deletéreas tales como la enfermedad de Alzheimer precoz, CADASIL (en inglés, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), y la enfermedad de Parkinson, se recogió una muestra de 10 cm 3 de sangre con anticoagulante (EDTA), para la posterior extracción del ADN. Las muestras con sangre total se rotularon con el nombre del paciente y la fecha y se almacenaron a 4 o C hasta la extracción de ADN. ...
Article
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Linkage analyses enable us to identify the loci that bestow susceptibility to certain diseases which are assumed to have a genetic aetiology by determining the cosegregation of alleles of specific markers within families. The aim of this study was to determine whether there is generalised idiopathic epilepsy (GIE) susceptibility in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions within an extended multigenerational family belonging to the Paisa community in Antioquia, a genetic isolate located in Colombia segregating for GIE with a strong capacity for detecting linkage. A family with a number of individuals affected by idiopathic epilepsy who visited the Instituto Neurológico de Antioquia was selected for study. An affected individual was required to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise the seizures electroencephalographically. Of the 106 individuals in this family that were included in the family tree, 76 were genotyped, 15 of whom were affected by generalised clonic tonic seizures and six were considered to be possibly affected. Results of the lod score were significantly negative for all the markers in relation to each model that was considered. The possibility of the genes located in the 8q22.1 -q24.23, 16p13.3 and 21q22.3 regions being responsible for the familial aggregation of GIE in this family was ruled out, which is in accordance with claims made in previous studies conducted on other families.
... No aparecen diferencias significativas entre los pacientes no diagnosticados y los diagnosticados con EA. [REV NEUROL 2004; GABA (15q11-q13). En este artículo presentamos los resultados del análisis de ligamiento realizado mediante microsatélites sobre una familia extendida multigeneracional que segrega epilepsia idiopática, perteneciente a la comunidad Paisa de Antioquia, un aislado genético localizado en Colombia [4,5], y con un fuerte poder para detectar ligamiento. ...
... Tras obtener el consentimiento informado por escrito de cada individuo de la familia Epi1, perteneciente a la comunidad Paisa en Medellín (Antioquia, Colombia), un aislado genético que ya se ha descrito [4,5,8,9], y con un efecto fundador para algunas mutaciones deletéreas, como la enfermedad de Alzheimer precoz (PS-1 E280A), CADASIL (notch3 C455R) y enfermedad de Parkinson (Parkin Cys212Tyr) [10][11][12], se le tomó una muestra de sangre de 10 cm 3 , con anticoagulante (EDTA), para la posterior extracción del ADN. Las muestras con sangre total se rotularon con el nombre del paciente y la fecha, y se almacenaron a 4 o C hasta la extracción de ADN. ...
Article
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Linkage analyses provide strong evidence of how genetic factors influence epilepsy, due to the fact that they involve the determination of the cosegregation of specific marker alleles with epilepsy within families. Our aim was to determine whether there was some kind of propensity to develop generalised idiopathic epilepsy (GIE) in the 15q22.1-q25.1 region in an extended multigenerational family from the Paisa de Antioquia community, which is a genetic isolate located in Colombia that segregates for GIE and has a strong capacity to detect linkage. We selected a family containing a number of individuals suffering from epilepsy who visited the Antioquia Neurological Institute. Each affected individual had to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or from partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise seizures electroencephalographically. Of the 106 individuals in this family who were included in the family tree, 76 were genotyped; 15 of them suffered from generalised clonic tonic seizures and six were considered as being possibly affected. Lod score results were significantly negative for all the markers in relation to each of the models under consideration. The possibility of the genes that code for the a-3, a-5 and b-4 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA3, CHRNA5 and CHRNB4) situated in the 15q region being responsible for the familial aggregation of GIE in this family, as has been suggested in previous studies in other families, was ruled out.
... Barranquilla's population is the result of a racial admixture between Aboriginal Amerindian communities with Spaniards and Africans, and later with Syrians-Lebanese, Sephardi Jews, Germans, Italians, and English immigrants [47,48]. The admixture composition of this community (~63% African with a vast Amerindian contribution) [49] suggests an ethnic heterogeneity [50,51] that substantially differs from that of the "Paisa" community, a genetic isolate from Colombia with a high prevalence of ADHD and a very small African ethnical background [52][53][54][55][56]. This study was approved by the Ethics Committee of Universidad Simón Bolívar at Barranquilla, Colombia (approval # 00032 of 13 October 2011). ...
Article
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Temporal processing (TP) is associated with functions such as perception, verbal skills, temporal perspective, and future planning, and is intercorrelated with working memory, attention, and inhibitory control, which are highly impaired in individuals with attention deficit hyperactivity disorder (ADHD). Here we evaluate TP measures as potential endophenotypes in Caribbean families ascertained from probands affected by ADHD. A total of 232 individuals were recruited and clinically evaluated using an extensive battery of neuropsychological tasks and reaction time (RT)-based task paradigms. Further, the heritability (genetic variance underpinning phenotype) was estimated as a measure of the genetics apportionment. A predictive framework for ADHD diagnosis was derived using these tasks. We found that individuals with ADHD differed from controls in neuropsychological tasks assessing mental control, visual-verbal memory, verbal fluency, verbal, and semantic fluency. In addition, TP measures such as RT, errors, and variability were also affected in individuals with ADHD. Moreover, we determined that only omission and commission errors had significant heritability. In conclusion, we have disentangled omission and commission errors as possible TP endophenotypes in ADHD, which can be suitable to assess the neurobiological and genetic basis of ADHD. A predictive model using these endophenotypes led to remarkable sensitivity, specificity, precision and classification rate for ADHD diagnosis, and may be a useful tool for patients’ diagnosis, follow-up, and longitudinal assessment in the clinical setting.
... ADHD children reportedly have an increased presence of the ADGRL3 rs6551665 GG genotype [130] but further studies are needed to confirm this finding. Other SNPs within ADGRL3 have also been shown to be associated with adult ADHD [39,131]. Common variants in the CDH13 gene have been reported by a Genome-Wide Association Scan of Quantitative Traits [54] and a Case-Control GWAS [132] to be associated with childhood ADHD. ...
Article
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the 'missing heritability' of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene-environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene-environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.
... Identification of different loss of heterozygosity regions suggests the possibility of locating homozygous causative variants within each respective area; however, the existence of such variants must be further investigated. The assumption of a single causative gene is best suited for nuclear families with multigenerational pedigrees affected with ADHD and genetically isolated for long periods of time, hence providing exceptionally effective power to detect linkage (Arcos-Burgos et al., 2002). The families that we recruited for this study were from a population with a high rate of consanguinity and endogamy, but a single causative gene may be hard to uncover as we are dealing with a multifactorial and heterogeneous disorder. ...
Article
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Aim: Genetic and clinical complexities are common features of most psychiatric illnesses that pose a major obstacle in risk-gene identification. Attention deficit hyperactivity disorder (ADHD) is the most prevalent child-onset psychiatric illness, with high heritability. Over the past decade, numerous genetic studies utilizing various approaches, such as genome-wide association, candidate-gene association, and linkage analysis, have identified a multitude of candidate loci/genes. However, such studies have yielded diverse findings that are rarely reproduced, indicating that other genetic determinants have not been discovered yet. In this study, we carried out sib-pair analysis on seven multiplex families with ADHD from Saudi Arabia. We aimed to identify the candidate chromosomal regions and genes linked to the disease. Patients and methods: A total of 41 individuals from multiplex families were analyzed for shared regions of homozygosity. Genes within these regions were prioritized according to their potential relevance to ADHD. Results: We identified multiple genomic regions spanning different chromosomes to be shared among affected members of each family; these included chromosomes 3, 5, 6, 7, 8, 9, 10, 13, 17, and 18. We also found specific regions on chromosomes 8 and 17 to be shared between affected individuals from more than one family. Among the genes present in the regions reported here were involved in neurotransmission (GRM3, SIGMAR1, CHAT, and SLC18A3) and members of the HLA gene family (HLA-A, HLA-DPA1, and MICC). Conclusion: The candidate regions identified in this study highlight the genetic diversity of ADHD. Upon further investigation, these loci may reveal candidate genes that enclose variants associated with ADHD. Although most ADHD studies were conducted in Other populations, our study provides insight from an understudied, ethnically interesting population.
... Various genetic models for ADHD have been proposed but none have emerged with strong support. Although often considered a complex trait without a clearly recognizable Mendelian model of inheritance, segregation analyses have provided some evidence for a single gene transmission model [53][54][55][56]. However, linkage studies have not identified such a major gene, although studies have been underpowered to detect even a modest degree of locus heterogeneity. ...
Article
ADHD and Autism have been considered as two separate disorders and the classification systems make them mutually exclusive. However, there is a long-standing literature on overlapping phenotypes, and a more recent genetic literature on rare variants that have been found in both. This review summarises the clinical, familial and recent genetic overlap and discusses what this might mean for future diagnosis and treatment.
... La WURS ha sido empleada en investigaciones en varios países, evidenciando una validez y confiabilidad al ser comparada con otros instrumentos. [111][112][113][114][115][116][117][118] En nuestro país se han realizado investigaciones en TDAH en la infancia y en adultos empleando la escala para describir las conductas de manera retrospectivas. 119,120 Estas investigaciones tienen como características a una población proveniente de un aislado genético, aspecto que no se reseña en otras investigaciones donde se empleó la escala, por tanto sería de gran utilidad la realización de estudios transculturales que permitan la comparación de las dos muestras colombianas, para identificar posibles diferencias y similitudes entre las variables y los resultados, debido a que la población perteneciente a la ciudad de Barranquilla, es considerada como una comunidad de inmigrantes multirracial y así validar los instrumentos como aspecto clave para establecer el fenotipo del TDAH en Colombia independiente de las diferencias culturales. ...
Article
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The behavioral questionnaires are effective tools to characterize the Attention Deficit Hyperactivity Disorder (ADHD) in adulthood. It was determined the behavioral characteristics of adults with ADHD in retrospect by using the Wender Utah Rating Scale (WURS). The sample consisted of 102 adults from 51 nuclear families in the city of Barranquilla. The diagnosis of ADHD was conducted using a structured psychiatric interview validated in Colombia, which is also used for genetic studies of ADHD. A neurological examination and a neuropsychological evaluation were made. The cutting scores were analyzed and the effect size, sensitivity and specificity of the scale were calculated. It was found that there are clinical and statistical significant differences in WURS scores, which showed large to enormous effect sizes. The scale distinguishes affected subjects from the unaffected ones, which proves the existence of ADHD symptoms in retrospect. It is important to highlight the WURS can be used as a tool for screening adult ADHD symptoms. However, it is necessary to complement its results with other tools for multimodal diagnostic testing.
... The association between markers at chromosome 4q13.2 (near LPHN3) and ADHD was first observed in a linkage study of a large multigenerational families in a population isolate, the Paisa from Colombia, where the prevalence of ADHD is high [Arcos-Burgos et al., 2002]. LPHN3 is a member of the LPHN subfamily of G-protein coupled receptors (GPCRs), which have been shown to be important for exocytosis of neurotransmitter regulation [Rahman et al., 1999;Linets'ka et al., 2002]. ...
Article
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Attention-deficit/hyperactivity disorder (ADHD) is a complex and heterogeneous disorder, affecting individuals across the life cycle. Although its etiology is not yet completely understood, genetics plays a substantial role. Pharmacological treatment is considered effective and safe for children and adults, but there is considerable inter-individual variability among patients regarding response to medication, required doses, and adverse events. We present here a systematic review of the literature on ADHD pharmacogenetics to provide a critical discussion of the existent findings, new approaches, limitations, and recommendations for future research. Our main findings are: first, the number of studies continues to grow, making ADHD one of the mental health areas with more pharmacogenetic studies. Second, there has been a focus shift on ADHD pharmacogenetic studies in the last years. There is an increasing number of studies assessing gene-gene and gene-environment interactions, using genome-wide association approaches, neuroimaging, and assessing pharmacokinetic properties. Third and most importantly, the heterogeneity in methodological strategies employed by different studies remains impressive. The question whether pharmacogenetics studies of ADHD will improve clinical management by shifting from trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains unanswered. © 2014 Wiley Periodicals, Inc.
... Another study involved 495 families, where a subgroup of 130 families was utilized and supported a sex-dependant Mendelian codominant model (Maher, Marazita, Moss, & Vanyukov, 1999). A third segregation analysis of 53 families from a genetic isolate has failed to reject a Mendelian dominant and codominant major gene model of inheritance, while rejecting multifactorial, nongenetic familial transmission, and various mixed models (Arcos-Burgos et al., 2002;Lopera et al., 1999;Maher, Marazita, Moss, & Vanyukov, 1999). Although these three studies were performed in different populations, with various methods to test inheritance, they converge in explaining the predisposition to ADHD as a consequence of a Mendelian factor. ...
Article
The intent of this review is to provide an overview for the practicing psychologist/psychiatrist regarding the complexities of and the most recent advances made in the study of the genetic basis of attention-deficit/hyperactivity disorder (ADHD). We review a variety of concepts including: (a) complexities involved in studying the genetics of ADHD, (b) evidence for a primarily genetic component of ADHD, (c) evidence suggesting that there are only a few genes with major effects contributing to ADHD, (d) identification of the best candidate genes, (e) linkage analysis for the identification of novel candidate genes, and (f) data on gene-environment interactions. It is now generally accepted that ADHD has a biological and even primarily genetic basis. However, despite the identification of several candidate genes, none of them seems to have a substantial effect and the exact etiology underlying ADHD has remained elusive. Genome-wide linkage analysis can help in the identification of novel candidate genes. While several independent groups have initiated these studies, we await further details and specific genes from fine-mapping studies. Most recently, researchers have been trying to identify gene by environment interactions to help understand ADHD. Replication of positive findings will be essential in teasing out these combinatorial influences. Ideally, one day specific genes with major effects and specific risk factors with which they interact will be identified and we will be able to implement personalized medicine. Knowledge of such genes will allow us to identify specific diagnostic biological markers. In addition, defining the target genes is the first step in developing novel drug therapies to treat the ADHD symptoms that lead to impairment. Furthermore, such markers could also identify at risk individuals at a younger age in order to implement treatments sooner to decrease the severity of ADHD symptoms or even to prevent future ADHD symptomatology.
... En la actualidad se considera que el TDAH está determinado genéticamente y existen marcadores que predicen la presentación clínica del trastorno, es decir, que el diagnóstico genético confirmaría el diagnóstico clínico. [20][21][22] No obstante, nuestro estudio destaca la importancia de hacer un diagnóstico formal de los síntomas conductuales en niños y niñas con RM ya que con mucha frecuencia no son considerados en la aproximación diagnóstica de estos pacientes 23 y en consecuencia no reciben el manejo adecuado. 24,25 De la misma forma, este trabajo presenta limitaciones a saber, el número reducido de niñas y niños evaluados, no se estudió la comorbilidad, se estudiaron sólo niños y niñas con RM leve y moderado y es posible que esta población no sea representativa de los casos de RM en la población general porque es probable que los niños y niñas con RM más sintomáticos sean llevados a consulta con el o la psiquiatra o que se omite la precisar el coeficiente intelectual en aquellos niños y niñas que muestran en la evaluación clínica pocas habilidades que sugieren el diagnóstico de RM severo. ...
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... Genetic, geographic, and demographic features of this self-designated, genetically isolated ''Paisa'' community have been described in detail elsewhere. [21][22][23][24] Today, most people in the State of Antioquia belong to the self-designated ''Paisa'' community. It is very important to point out that this genetic isolate is really a community dispersed from north to south in Colombia. ...
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... Wie sich bereits aus Zwillings-und Adoptionsstudien ableiten lässt, muss bei AHDS von überwiegend genetischen Ursachen ausgegangen werden [13,14]. Es liegt jedoch kein monogener Erbgang vor; vielmehr sind zahlreiche, sich gegenseitig beeinflussende Genvarianten beteiligt. ...
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Attention-deficit hyperactivity disorder (ADHD) is a chronic behavioural disorder diagnosed in 4.8 % of German children and adolescents. Although many studies indicate primarily a neurobiological etiology, the disorder cannot be diagnosed on the basis of specific markers. The principal aspect of diagnosis is the experienced clinician who must also take the differentiation of other behavioural disorders into account. In addition to inheritance, other known risk factors are nicotine exposition in pregnancy, adverse psychosocial conditions and birth complications. Protective factors are cognitive abilities, positive social contacts, and early treatment. The necessary structures in community support are developing; however, substantial enhancement is needed. Studies on quality of life indicate that ADHD should not be reduced to core symptoms since affected children are impaired in almost all areas of daily life.
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Objective: The aim of this study is to contrast the genetics of neuropsychological tasks in individuals from nuclear families clustering ADHD in a Caribbean community. Method: We recruited and clinically characterized 408 individuals using an extensive battery of neuropsychological tasks. The genetic variance underpinning these tasks was estimated by heritability. A predictive framework for ADHD diagnosis was derived using these tasks. Results: We found that individuals with ADHD differed from controls in tasks of mental control, visuospatial ability, visuoverbal memory, phonological and verbal fluency, verbal and semantic fluency, cognitive flexibility, and cognitive ability. Among them, tasks of mental control, visuoverbal memory, phonological fluency, semantic verbal fluency, and intelligence had a significant heritability. A predictive model of ADHD diagnosis using these endophenotypes yields remarkable classification rate, sensitivity, specificity, and precision values (above 80%). Conclusion: We have dissected new cognitive endophenotypes in ADHD that can be suitable to assess the neurobiological and genetic basis of ADHD.
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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.Keywords: ADHD; complex trait; gene; LPHN3; genetics; latrophilin
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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.
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Die Aufmerksamkeitsdefizit/-Hyperaktivitätsstörung (ADHS) ist eine chronische Verhaltensstörung, die in Deutschland bei 4,8 % aller Kinder und Jugendlichen diagnostiziert wird. Obwohl viele Studien überwiegend neurobiologische Ursachen für ADHS nahelegen, lässt sich die Erkrankung noch nicht anhand entsprechender biologischer Marker diagnostizieren. Im Mittelpunkt der Diagnose steht die Einschätzung eines erfahrenen Klinikers, wobei die Abgrenzung zu anderen psychischen Erkrankungen bedeutsam ist. An Risikofaktoren sind neben der Veranlagung u. a. die Nikotinexposition des Kindes während der Schwangerschaft, ungünstige psychosoziale Umstände und Geburtskomplikationen bekannt. Als Schutzfaktoren haben sich die kognitive Begabung, günstige Sozialkontakte und eine frühe Behandlung erwiesen. Die erforderlichen Versorgungsstrukturen entwickeln sich, bedürfen aber noch erheblicher Verbesserung. Studien über die Lebensqualität betroffener Kinder zeigen, dass diese in nahezu allen Bereichen erheblich eingeschränkt ist. Attention-deficit hyperactivity disorder (ADHD) is a chronic behavioural disorder diagnosed in 4.8 % of German children and adolescents. Although many studies indicate primarily a neurobiological etiology, the disorder cannot be diagnosed on the basis of specific markers. The principal aspect of diagnosis is the experienced clinician who must also take the differentiation of other behavioural disorders into account. In addition to inheritance, other known risk factors are nicotine exposition in pregnancy, adverse psychosocial conditions and birth complications. Protective factors are cognitive abilities, positive social contacts, and early treatment. The necessary structures in community support are developing; however, substantial enhancement is needed. Studies on quality of life indicate that ADHD should not be reduced to core symptoms since affected children are impaired in almost all areas of daily life.
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The diagnostic criteria for the attentional deficit hyperactivity disorder (ADHD), were defined by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders fourth version (DSM-IV) and World Health Organization in the ICD-10. The American Psychiatric Association used an internal validity analysis to select specific behavioral symptoms associated with the disorder and to build five cross-cultural criteria for its use in the categorical diagnosis. The DSM has been utilized for clinicians and researchers as a valid and stable approach since 1968. We did a systematic review of scientific literature in Spanish and English, aimed to identify the historical origin that supports ADHD as a psychiatric construct. This comprehensive review started exploring the concept of minimal brain dysfunction, hyper-activity, inattention, impulsivity since 1932 to 2011. This paper summarize all the DSM versions that include the definition of ADHD or its equivalent, and it point out the statistical and methodological approach implemented for defining ADHD as a valid epidemiological and psychometric construct. Finally the paper discusses some considerations and suggestions for the new versions of the manual.
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The diagnostic criteria for the attention deficit/hyperactivity disorder (ADHD) were defined by the American Psychiatric Association in the Diagnostic and Statistical Manual of Mental Disorders, fourth version. ADHD is a neuro-psychiatric disorder associated with impairments in everyday life and behavioral dysregulation (i.e. inattention, hyper-activity and impulsivity), and it has showed empirical evidence from clinical, pharmacological, and psychometric studies. Nevertheless, the role of neurobiological impairments in the presentation of the symptoms remains unclear. For this paper, the authors reviewed Spanish and English literature that support the neurobiological validity of the disorder, aimed to present evidence associated with its cognitive and behavioral phenotype (e.g. in: neuropsychology, electrophysiology, structural and functional magnetic resonance imaging, neurochemistry and genetics). Additionally, an integrative theoretical clinical and scientific proposal is presented. Finally, the introduction of neurobiological marker as part of the definitive diagnosis is suggested, as a started point for the identification of therapeutic targets.
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While genetic epidemiological studies demonstrate a substantial degree of genetic predisposition for attention-deficit/hyperactivity disorder (ADHD), they also suggest that the genetics are complex and may differ between populations or ethnic groups. This study describes the phenomenology of siblings with ADHD from the genetically isolated population of the Central Valley of Costa Rica. Rates of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined ADHD subtypes and comorbid conditions were calculated in a sample of 157 ADHD-affected children (probands and siblings) recruited for genetic studies using standardized approaches. Sib-sib comparisons and logistic regressions were conducted to identify significant patterns of concordance. Combined-type ADHD (69.5%) was the most common subtype among probands, followed by the inattentive (27.4%), and hyperactive-impulsive (3.2%) subtypes. Anxiety disorders were prevalent (55.9%), as were disruptive behavior disorders (30.9%) and Tourette disorder (17.0%). Probands and siblings showed high sib-sib concordance for anxiety disorders. ADHD in Costa Rica is similar in clinical and demographic characteristics to ADHD seen in other parts of the world, although the rates of co-occurring psychiatric disorders differ somewhat from those previously reported in Latin American samples. Comorbid anxiety is prevalent, with high rates of sib-sib concordance, and may represent a distinct, homogeneous subgroup suitable for genetic studies.
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During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment protocols may take years to become routine clinical practice. However, when taken together, recent successes in genomics, pharmacogenomics, and genetic epidemiology have the potential (1) to prevent comorbid consequences of ADHD, (2) to individualize therapies for patients with ADHD, and (3) to define new epidemiological policies to aid with the impact of ADHD on society. Here, we present an overview of how genetic research may affect and improve the quality of life of patients with ADHD: as an example, we use the discovery of LPHN3, a new gene in which variants have recently been shown to be associated with ADHD.
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Some perinatal factors have been associated with attention d ficit/hyperactivity disorder (ADHD). To estimate the association between perinatal factor and ADHD diagnosis in school, aged 6 to 11 years, children from Medell n city (Colombia). A randomized sample of 200 cases, 6 to 11 year old, with standardized ADHD diagnosis was selected. A randomized sample of 200 control children, 6 to 11 year old, was selected from a data base of 70 schools of Medell n city. The same diagnostic protocol was administered to controls. A questionnaire with questions about pregnancy, delivery an neonatal period was given to the mothers. Data were analyzed using cross tabulation and stepwise logistic multiple regression analyses. Miscarriage symptoms, premature delivery symptoms, severe flu attacks (cold with fever, without virus confirmation), tobacco abuse, alcohol abuse (to become drunk), minor congenital malformations, neonatal seizures and hospitalizations during newborn period were factors associated with ADHD diagnosis (p< 0.05). However, stepwise logistic multiple regression analysis selected a block of variables formed by premature delivery symptoms, severe flu attacks and neonatal seizures as significant perinatal risk factors (p< 0.01) for ADHD diagnosis.
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Allele and genotype frequencies of the VNTR polymorphism in the third exon of human DRD4 gene were determined in 544 individuals living in Russia (Russians, Bashkirs, Tatars, and Mordovians) and in the neighboring countries (Kazakhs and Ukrainians). The data obtained were compared with the allele frequency distribution patterns reported for the populations of Eurasia. Similarly to other Eurasian populations, in our population samples R4 allele was prevalent (64 to 87%). The frequency of this allele in the populations of Western Europe constitute 61 to 71%, while in the populations of Asia it varies from 74 to 96%. In this respect, the populations studied occupied the intermediate position. In the samples examined the R7 allele frequency decreased from 7% in Ukrainians to 1% in Bashkirs, while in Kazakhs and Mordovians the allele was absent. This finding was consistent with the R7 allele distribution pattern in the populations of Eurasia, characterized by higher frequency in the West and lower frequency or absence of the allele in the East. In the group of 22 Eurasian populations, the R7 allele frequency negatively correlated with the frequency of the R4 allele (r = -0.86 at P < 0.001). Unlike the R4 and R7 alleles, the frequency of which changed in the eastward direction, the R2 allele frequency distribution displayed slightly expressed latitudinal increase southwards. The DRD4 genotype distribution deviated from the equilibrium in most of the samples examined. In some samples, statistically significant increase of the R2/R2 homozygotes frequency was demonstrated. One of the possible explanations of this phenomenon is assortative mating with respect to phenotypic (behavioral) allele manifestation. The data obtained can serve as the basis for the investigation of the possible role of the DRD4 alleles as the risk factors for the development of alcoholism and other types of addictions.
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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.
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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. 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. 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. 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.
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This study assesses the validity of the Behavioral Assessment System for Children-parent and teacher questionnaires for attention-deficit hyperactivity disorder diagnosis in a randomized sample of 344 Colombian children (145 cases, 199 controls), males and females, ages 6 to 11, with an estimated Wechsler Full Scale Intelligence Quotient over 70. The assessment protocol for both groups included psychiatric, neurologic, and psychological interviews, parent and teacher rating forms, and an Attention-Deficit Hyperactivity Disorder Checklist. All Behavioral Assessment System for Children-parent and teacher dimensions, except withdrawal and somatization, significantly differentiated cases and controls. Parents and teachers rated attention-deficit hyperactivity disorder combined type children as significantly more aggressive. Both questionnaires had good discriminant accuracy for detecting cases and control children, but accuracy for discriminating between attention-deficit hyperactivity disorder subtypes was poor. The Behavioral Assessment System for Children-parent and teacher questionnaires for 6- to 11-year-olds may be useful tools for diagnosing the presence of attention-deficit hyperactivity disorder. Additional assessment methods will be needed to discriminate between the subtypes.
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Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%) while observed in only 10.6% in outbred American and European populations. Furthermore, haplogroups J and K are less frequent (1.0%) than in the outbred data set (9.4-11.2%). Affected case matrilines and unaffected control lines were chosen from pedigrees to test whether specific haplogroups and their defining SNPs confer risk of AD. We did not observe frequency differences between AD cases compared to controls overall or when stratified by sex. Therefore, we suggest that the genetic effect responsible for AD dementia in the affected Amish pedigrees is unlikely to be of mitochondrial origin and may be caused by nuclear genetic factors.
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Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder whose essential characteristic is a persistent pattern of inattention or hyperactivity and impulsiveness. Recent studies into prevalence carried out on the Antioquian population by our group found an overall prevalence of 15.8%, which confirms ADHD as one of the most frequent problems in infancy. The cause of this disorder is still not altogether clear; familial aggregation of ADHD points towards a genetic component. Although to date no model of inheritance has been defined, its high prevalence rate, the difficulties involved in its diagnosis and its effects on the cognitive functions, as well as the social and educational repercussions, make this disorder a problem in children's public health. Our aim was to carry out power simulations to detect genetic linkage. The Slink programme, which is part of Linkage package, was used in six families from the city of Medellín Antioquia, which is a region where a founding effect is likely to have taken place; this makes it a strategic zone for genetic linkage studies in complex diseases such as ADHD. Assuming the population to be homogenous, the lod score (Z) is greater than 3 (Z>3) and individual lod score values of between 0 and 6 were obtained for each family. In this paper we discuss the benefits of having multigenerational families, in Antioquia, to conduct gene mapping studies and we examine the different strategies to be developed with the findings reported here.
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Attention Deficit and Hyperactivity Disorder (ADHD) is a common idiopathic childhood neurodevelopmental disorder, exacting a significant clinical and public health toll. It impairs schooling and social adaptation, resulting in high rates of depression, conduct disorder, school dropouts, and substance abuse, and necessitating exposure of many children to prolonged courses of stimulant psychotropic medication. Although the biological basis of ADHD is unknown, it has been shown to possess considerable heritability. Candidate gene association studies proved to be a productive strategy leading to replicated association findings of genetic loci contributing to susceptibility to ADHD. Based on the mechanism of action of stimulant drugs effective in the alleviation of ADHD symptoms, current association studies have focused mainly on dopaminergic genes. Promising exploratory findings have also been reported for genes affecting other neurotransmitter systems. The current article reviews the rationale, methodology, and main findings in the field, and outlines future directions. Locating the actual genes mediating ADHD susceptibility will have far reaching implications for understanding the pathophysiology of ADHD as well as for understanding mechanisms of therapeutic drug action and genetic determinants of response.
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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. 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. 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. 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.
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Three independent complex segregation analyses found that the cause of Attention Deficit/Hyperactivity Disorder (ADHD) was the presence of major genes interacting with environmental influences. In order to identify potential environmental risk factors for ADHD in the Paisa community--a very well described, genetically isolated group--we randomly selected a sample of 486 children between 6 and 11 years of age. This group included 200 children with ADHD (149 males and 51 females) and 286 healthy controls (135 males and 151 females). The ADHD DSM-IV diagnosis was obtained using the DICA and BASC evaluation instruments, and the children's mothers or grandmothers filled out a questionnaire on each child's exposure to prenatal, neonatal, and early childhood risk factors. The data were analyzed using cross tabulation and stepwise logistic multiple-regression analyses. Cross tabulation associated ADHD with a variety of factors, including miscarriage symptoms, premature delivery symptoms, maternal respiratory viral infection, moderate to severe physical illness in the mother during gestation, prenatal cigarette and alcohol exposure, neonatal seizures, asphyxia or anoxia, severe neonatal illness, mild speech retardation, moderate brain injury, and febrile seizures (odds ratio >or= 2, P < 0.05). Stepwise logistic multiple-regression analysis also uncovered a block of variables, including male gender, maternal illnesses, prenatal alcohol exposure, mild speech retardation, febrile seizures, and moderate brain injury (odds ratio >or= 2.0, P < 0.05). Future studies on the risk of developing ADHD must include these environmental factors as covariates.
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The Composite International Diagnostic Interview (CIDI), written at the request of the World Health Organization/US Alcohol, Drug Abuse, and Mental Health Administration Task Force on Psychiatric Assessment Instruments, combines questions from the Diagnostic Interview Schedule with questions designed to elicit Present State Examination Items. It is fully structured to allow administration by lay interviewers and scoring of diagnoses by computer. A special Substance Abuse Module covers tobacco, alcohol, and other drug abuse in considerable detail, allowing the assessment of the quality and severity of dependence and its course. This article describes the design and development of the CIDI and the current field testing of a slightly reduced "core" version. The field test is being conducted in 19 centers around the world to assess the interviews' reliability and its acceptability to clinicians and the general populace in different cultures and to provide data on which to base revisions that may be found necessary. In addition, questions to assess International Classification of Diseases, ninth revision, and the revised DSM-III diagnoses are being written. If all goes well, the CIDI will allow investigators reliably to assess mental disorders according to the most widely accepted nomenclatures in many different populations and cultures.
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In order to assess the genetic etiology of attention deficit hyperactivity disorder (ADHD), the basic regression model for the analysis of selected twin data (DeFries & Fulker, 1985, 1988) was fitted to questionnaire data (DICA: Diagnostic Interview for Children and Adolescents; Herjanic, Campbell, & Reich, 1982) for 37 identical and 37 fraternal twin pairs tested in the Colorado Reading Project. Results of this analysis suggest that ADHD is highly heritable. Moreover, adjusting DICA scores for either IQ or reading performance differences did not substantially change parameter estimates. In future analyses of larger data sets, distinguishing between possible subtypes of attentional problems (e.g., ADD with or without hyperactivity) may facilitate tests of more searching etiological questions.
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The CIDI is a fully standardised diagnostic interview designed for assessing mental disorders based on the definitions and criteria of ICD-10 and DSM-III-R. Field trials with the CIDI have been conducted in 18 centres around the world, to test the feasibility and reliability of the CIDI in different cultures and settings, as well as to test the inter-rater agreement for the different types of questions used. Of 590 subjects interviewed across all sites and rated by an interviewer and observer, 575 were eligible for analysis. The CIDI was judged to be acceptable for most subjects and was appropriate for use in different kinds of settings. Many subjects fulfilled criteria for more than one diagnosis (lifetime and six-month). The most frequent lifetime disorders were generalised anxiety, major depression, tobacco use disorders, and agoraphobia. Percentage agreements for all diagnoses were above 90% and the kappa values were all highly significant. No significant numbers of diagnostic disconcordances were found with lifetime, six-month, and four-week time frames.
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This study tested hypotheses about patterns of familial association between attention deficit disorder (ADD) and anxiety disorders among 356 first-degree relatives of 73 clinically referred children with ADD and 26 normal comparison children. Through structured diagnostic interviews with trained raters, relatives were assessed for adult and childhood psychopathology. After stratifying the sample of ADD probands into those with anxiety disorders and those without, the authors examined patterns of aggregation of ADD and anxiety disorders in the relatives of these probands as well as in the relatives of the normal comparison subjects. Familial risk analyses revealed that 1) familial risk for anxiety disorders was higher among all ADD probands than among the normal subjects; 2) familial risk for ADD was similar in the relatives of the ADD probands and of the probands with ADD and anxiety disorder; 3) the relatives of the ADD probands with and without anxiety disorders were at greater risk for ADD than the relatives of the normal subjects; 4) the risk for anxiety disorders was two times higher in the relatives of the probands who had ADD with anxiety disorder than in those of the ADD probands without anxiety disorders; and 5) there was a tendency for ADD probands' relatives who themselves had ADD to have a higher risk for anxiety disorders than ADD probands' relatives who did not have ADD (cosegregation). The results were most consistent with the hypotheses indicating that ADD and anxiety disorders segregate independently in families.
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The Composite International Diagnostic Interview (CIDI), written at the request of the World Health Organization/US Alcohol, Drug Abuse, and Mental Health Administration Task Force on Psychiatric Assessment Instruments, combines questions from the Diagnostic Interview Schedule with questions designed to elicit Present State Examination items. It is fully structured to allow administration by lay interviewers and scoring of diagnoses by computer. A special Substance Abuse Module covers tobacco, alcohol, and other drug abuse in considerable detail, allowing the assessment of the quality and severity of dependence and its course. This article describes the design and development of the CIDI and the current field testing of a slightly reduced "core" version. The field test is being conducted in 19 centers around the world to assess the interviews' reliability and its acceptability to clinicians and the general populace in different cultures and to provide data on which to base revisions that may be found necessary. In addition, questions to assess International Classification of Diseases, ninth revision, and the revised DSM-III diagnoses are being written. If all goes well, the CIDI will allow investigators reliably to assess mental disorders according to the most widely accepted nomenclatures in many different populations and cultures.
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This article reports on the development and reliability of the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions. The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability. The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings. A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria-based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder. Reliabilities using algorithms were excellent (0.73 to 0.95), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability. A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions. The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.
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To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene. Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD. Community based in Antioquia, Colombia. A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected. Age at onset, neuropsychological profile, neurologic history, and examination. The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.
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The purposes of this study were (a) to estimate the prevalence of Attention-Deficit/Hyperactivity Disorder (AD/HD) symptoms in the general preschool and school population; and (b) to analyze the influence of gender, age, and socioeconomic status (SES) variables on AD/HD symptoms. Out of the 80,000 preschool and schoolchildren living in Manizales, Colombia, a random sample of 540 children was selected. Two gender, three age (4- to 5-year olds, 6- to 11-year olds, and 12- to 17-year olds), and three SES (low, middle, and high) groups were used. The 18 DSM-IV symptoms corresponding to AD/HD Criterion A were assessed on a scale of 0 (never) to 3 (almost always). All three demographic variables established statistically significant differences: AD/HD symptoms were more frequent in 6- to 11-year-old, low-SES, male participants. DSM-IV Criterion A for AD/HD was fulfilled by 19.8% of the boys and 12.3% of the girls. However, this difference was marginally significant only in the AD/HD Subtype I: Combined. It was concluded that demographic variables are significant correlates of the AD/HD diagnosis. The prevalence found in this study was higher than usually reported, even though only the symptomatic DSM-IV AD/HD criterion was analyzed. We failed to confirm the assumed AD/HD gender ratio.
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This article reviews controlled, prospective follow-up studies of children with attention-deficit disorders (ADHD) into young adulthood and adulthood. In their late teens, those with ADHD as children, compared with non-ADHD comparisions, show relative deficits in academic and social functioning. In addition, about two-fifths of these children continue to experience ADHD symptoms, and a significant minority demonstrate pervasive antisocial behaviors, including drug abuse. Many of these same difficulties persist into adulthood. Compared with the comparisons, former ADHD probands complete less formal schooling, hold lower ranking occupational positions, and continue to exhibit poor social skills, antisocial personality, and symptoms of the childhood syndrome. On the other hand, as adults, nearly all former cases are gainfully employed, some in higher level positions, and a full two-thirds show no evidence of any mental disorder. Although relative deficits are seen in early to middle adolescence, young adulthood, and adulthood, childhood ADHD does not preclude achieving one's educational and vocational goals, and the majority of these children do not experience emotional or behavioral problems by their mid-twenties.
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Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attention-deficit/hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing/haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination/mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations/mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold "younger" than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.
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This article reviews controlled, prospective follow-up studies of children with attention-deficit disorder (ADHD) into young adulthood and adulthood. In their late teens, those with ADHD as children, compared with non-ADHD comparisions, show relative deficits in academic and social. functioning. In addition, about two-fifths of these children continue to experience ADHD symptoms, and a significant minority demonstrate pervasive antisocial behaviors, including drug abuse. Many of these same difficulties persist into adulthood. Compared with the comparisons, former ADHD probands complete less formal schooling, hold lower ranking occupational positions, and continue to exhibit poor social skills, antisocial personality, and symptoms of the childhood syndrome. On the other hand, as adults, nearly all former cases are gainfully employed, some in higher level positions, and a full two-thirds show no evidence of any mental disorder. Although relative deficits are seen in early to middle adolescence, young adulthood, and adulthood, childhood ADHD does not preclude achieving one's educational and vocational goals, and the majority of these children do not experience emotional or behavioral problems by their mid-twenties.
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Introduction and objective. In order to elucidate the genetic and environmental components involved in the susceptibility to develop attention deficit hyperactivity disorder (ADHD), a complex segregation analysis on nuclear families (n = 53) ascertained from affected probands belonging to Medellin, in the Antioquian State, Colombia, was performed. Methods and results. Models of cohort effect (non-inheritance), multifactorial, recessive major gene, non-major gene component and non-transmission of major gene were rejected. Contrarily, dominant and codominant major gene models anti non-multifactorial component could not be rejected. Thus, the better model fitting the data was that of the major gene (dominant/codominant). This major gene explains more than 99,99% of the the ADHD phenotypic variance (value of heritability in the mixed model equal to 0.007%), which permit to assume a low aport of the environmental component to the phenotype ADHD. Gene frequency of the major gene was 3% in the general population of Antioquia and its penetrance was closed to 30%. Conclusion. Some cautions and aspects related to the bias of the interview and diagnosis of the parents are discussed.
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Chocó State, on the Colombian Pacific Coast, considered one of the most inhospitable regions of the world, is inhabited mostly by descendants of African slaves introduced in the 16th and 17th c. A.D. Polymorphisms of classical markers (blood groups AB0, Rh, MNS, Fy, K, Jk, Lu, Wr, Js, Kp, and P, serum proteins Tf, HPA * and Gc) analyzed in a sample of 130 show that the genetic constitution of Chocó is similar to that of occidental Africa. Admixture with Amerindian and European groups occurred, as shown by the presence of genes distinctive of these groups and by the estimation of racial admixture proportions. Evidence of evolutionary forces acting on HPA * was detected. Thus, we present strong evidence confirming that the present genetic structure of this community is the result of the interaction between natural selection and racial admixture.
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• With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD+AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the agecorrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD+AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD+AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.
Article
Objectives. —To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene.Design. —Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD.Setting. —Community based in Antioquia, Colombia.Patients. —A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected.Main Outcome Measures. —Age at onset, neuropsychological profile, neurologic history, and examination.Results. —The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent.Conclusions. —Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.
Article
We performed segregation analysis on 495 nuclear families, ascertained for the father's substance abuse diagnosis, in an attempt to determine the role of genetic and other influences in determining the variability of DSM-III-R-defined attention deficit hyperactivity disorder (ADHD). For our analyses, ADHD was treated as a quantitative variable, utilizing the semicontinuous scale provided by the 15-item symptom count within DSM-III-R. Analyses consisted of both class A and class D regressive models for which covariate effects (socioeconomic status) and sex dependence were estimated. Segregation analysis of the quantitative trait (ADHD symptom count) in the entire data set supported a transmissible non-Mendelian major effect. Models which were sex-dependent and included covariate effects provided the best fit to the data. In addition, similar analyses were performed on a 130-nuclear family subgroup of the data set in which at least one of the members of the nuclear family met DSM-III-R diagnostic criteria for ADHD. The sex-dependent Mendelian codominant model was best supported by the data, while other models could be rejected. Incorporating covariate effects did not provide a better fit for the data. Thus, this study is consistent with Mendelian transmission of ADHD symptom count in a clinically relevant population. Overall, our results support the presence of a heritable continuous trait of which ADHD represents an extreme. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:71–78, 1999. © 1999 Wiley-Liss, Inc.
Article
Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD)1,2 and are associated with increased levels of amyloid β-peptides (Aβ) ending at residue 42 (Aβ42) in plasma and skin fibroblast media of gene carriers3. AP42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A1340 (ref. 4), resulting in the formation of innumerable neuritic plagues. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred5 bearing the codon 280 Glu to Ala substitution (G1u280A1a) PS1 mutation2. Using antibodies specific to the alternative carboxy-termini of Aβ, we detected massive deposition of Aβ42, the earliest and predominant form of plague Aβ to occur in AD (ref. 6-8), in many brain regions. Computer-assisted quantification revealed a significant increase in Aβ42, but not Aβ40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous Aβ42-reactive plagues, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased Aβ42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the β-amyloid precursor protein at the C-terminus of Aβ to favor deposition of Aβ42.
Article
Although family, twin and adoption studies suggest that genetic factors are involved in attention deficit hyperactivity disorder, further evidence is needed to demonstrate that its familial transmission is consistent with known genetic mechanisms. We applied segregation analysis to a sample of 257 children and their 808 first-degree relatives. Interviews of subjects with DSM-III-R-based structured interviews provided the basis for psychiatric diagnosis. We analyzed these family data with the mixed model, as implemented in the computer program POINTER and a Class A regressive logistic model as implemented in the computer program REGTL. Our results indicate that the familial distribution of DSM-III-R attention deficit hyperactivity disorder is consistent with the effects of a single major gene. We can reject multifactorial polygenic transmission, non-familial environmental transmission, and cultural transmission. (C) Lippincott-Raven Publishers.
Article
A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997. © 1997 Wiley-Liss, Inc.
Article
The short variant of a functional length polymorphism in the promoter region of the serotonin transporter has been associated with several behavioural and psychiatric traits, including bipolar mood disorder. The same short allele has also been implicated as a modifier of the bipolar phenotype. Here we evaluate the etiologic/modifier role of this polymorphism in a case (N=103) / control (N=112) sample for bipolar mood disorder (type I) collected from an isolated South American population. We did not detect an association between bipolar disorder and the 5-HTT promoter polymorphism in this sample. However, an excess of the short allele was seen in younger cases and in cases with psychotic symptoms. When combined with data from the literature, the increased frequency of the short allele in patients with psychotic symptoms was statistically significant.
Article
The contribution of a parental population in the gene pool of a hybrid population which arose by hybridization with one or more other populations is estimated here at the population level from the probability of gene identity. The dynamics of accumulation of such admixture is studied incorporating the fluctuations due to finite size of the hybrid population. The method is illustrated with data on admixture in Cherokee Indians.
Article
We examined the sensitivity and specificity of the Wisconsin Card Sorting Test (WCST) as a measure of frontal lobe damage in 91 subjects with stable focal brain lesions. Anatomical information about the location and extent of brain damage was obtained from MR and CT transparencies. No significant differences in WCST performance were found between subjects with frontal vs. nonfrontal damage. Some subjects with extensive frontal lobe damage performed well on the WCST, and some subjects with damage outside of the frontal lobes failed. The optimal cutoff scores for discriminating frontal from nonfrontal subjects correctly classified only 62% of the subjects. Further analysis of WCST performances associated with damage to various subregions of the frontal lobes also failed to reveal any reliable relationships. These findings indicate that performance on the WCST cannot be interpreted in isolation as an index of frontal lobe damage.
Article
Attention deficit hyperactivity disorder is a heterogeneous disorder of unknown etiology. Little is known about the comorbidity of this disorder with disorders other than conduct. Therefore, the authors made a systematic search of the psychiatric and psychological literature for empirical studies dealing with the comorbidity of attention deficit hyperactivity disorder with other disorders. The search terms included hyperactivity, hyperkinesis, attention deficit disorder, and attention deficit hyperactivity disorder, cross-referenced with antisocial disorder (aggression, conduct disorder, antisocial disorder), depression (depression, mania, depressive disorder, bipolar), anxiety (anxiety disorder, anxiety), learning problems (learning, learning disability, academic achievement), substance abuse (alcoholism, drug abuse), mental retardation, and Tourette's disorder. The literature supports considerable comorbidity of attention deficit hyperactivity disorder with conduct disorder, oppositional defiant disorder, mood disorders, anxiety disorders, learning disabilities, and other disorders, such as mental retardation, Tourette's syndrome, and borderline personality disorder. Subgroups of children with attention deficit hyperactivity disorder might be delineated on the basis of the disorder's comorbidity with other disorders. These subgroups may have differing risk factors, clinical courses, and pharmacological responses. Thus, their proper identification may lead to refinements in preventive and treatment strategies. Investigation of these issues should help to clarify the etiology, course, and outcome of attention deficit hyperactivity disorder.
Article
With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities.
Article
I describe a simulation method to estimate the power to detect linkage given a set of pedigrees of known structure and for which family history data may be available. This method can be applied to autosomal and X-linked dominant diseases; depending on the pedigrees under consideration, it will often be applicable for autosomal and X-linked recessive diseases. This power calculation can most usefully be undertaken after family history data are gathered, but prior to examination and testing of pedigree members to obtain marker information. Of key importance, the power calculation is straightforward to carry out and not too time-consuming; it is practical even on a microcomputer. The result of the power calculation is an objective answer to the question: Will my families be sufficient to demonstrate linkage?
Article
Over the past 3 decades, the development of reliable and cross-culturally applicable diagnostic criteria and instruments for the assessment of mental disorders has been one of the major goals of the WHO mental health programme. The most important step in this endeavour of WHO was the production of the ICD-10 Classification of Mental and Behavioural Disorders and the following instruments: Composite International Diagnostic Interview (CIDI), Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and International Personality Disorder Examination (IPDE). This article outlines the basic characteristics of the latest editions of CIDI, SCAN and IPDE and provides descriptions of their newly developed versions and modules.
Article
In an attempt to surmount the problem of retrospectively establishing the childhood diagnosis of attention deficit hyperactivity disorder, the authors constructed the 61-item Wender Utah Rating Scale (WURS) for adults to use to describe their own childhood behavior. In this paper they present their initial data collection and evaluation of the instrument's validity. The scale was administered to 81 adult outpatients with attention deficit hyperactivity disorder, 100 "normal" adults, and 70 psychiatric adult outpatients with unipolar depression. The authors analyzed data from the 25 items of the scale that showed the greatest difference between the patients with attention deficit hyperactivity disorder and the normal comparison subjects and the relationship between the WURS and the patients' parents' judgment of childhood activity as measured by the Parents' Rating Scale. The patients with attention deficit hyperactivity disorder had significantly higher mean scores on all 25 items than did the two comparison groups. The difference between the mean total scores of the patients with attention deficit hyperactivity disorder and the normal subjects was also highly significant. A cutoff score of 46 or higher correctly identified 86% of the patients with attention deficit hyperactivity disorder, 99% of the normal subjects, and 81% of the depressed subjects. Correlations obtained between WURS scores and Parents' Rating Scale scores were moderate but impressive. The ability of WURS scores to predict response to methylphenidate replicated the authors' finding regarding the ability of Parents' Rating Scale scores to predict response to pemoline. The WURS is sensitive in identifying childhood attention deficit hyperactivity disorder and may be useful in recognizing attention deficit hyperactivity disorder in patients with ambiguous adult psychopathology.
Article
To summarize knowledge about attention deficit disorder in the areas of epidemiology, etiology, clinical predictors, assessments, natural history and outcome, and management. A literature review of articles, books, and chapters primarily published in the past 10 years was completed. Articles presenting new information, most relevant to clinical practice, were reviewed. Key findings in the areas listed above are presented. Major advances have been made in all areas. The clinical picture has been refined and developmental manifestations have been delineated. Patterns of comorbidity have been detailed. Various etiological factors, particularly in the biological area, have been investigated. Multimodal management has been promulgated as the treatment of choice.
Article
The allelic frequencies of 14 polymorphic loci were obtained for the Paisa community (Antioquia, Colombia) and compared with those of Caucasoids, Negroids and Amerindians as an approach to better understand its ancestral origin. Data pertaining to Caucasoids included Basques, Spaniards and Jews, historically assumed to be the ancestors of Paisas. These comparisons suggested that the Paisa community is a Caucasoid group with very low Amerindian or Negroid contributions. Spaniards or Basques and, to a lesser extent, Sephardims seem to have been their most probable ancestors.
Article
To investigate heritability and continuum versus categorical approaches to attention-deficit hyperactivity disorder (ADHD), using a large-scale twin sample. A cohort of 1,938 families with twins and siblings aged 4 to 12 years, recruited from the Australian National Health and Medical Research Council Twin Registry, was assessed for ADHD using a DSM-III-R-based maternal rating scale. Probandwise concordance rates and correlations in monozygotic and dizygotic twins and siblings were calculated, and heritability was examined using the De Fries and Fulker regression technique. There was a narrow (additive) heritability of 0.75 to 0.91 which was robust across familial relationships (twin, sibling, and twin-sibling) and across definitions of ADHD as part of a continuum or as a disorder with various symptom cutoffs. There was no evidence for nonadditive genetic variation or for shared family environmental effects. These findings suggest that ADHD is best viewed as the extreme of a behavior that varies genetically throughout the entire population rather than as a disorder with discrete determinants. This has implications for the classification of ADHD and for the identification of genes for this behavior, as well as implications for diagnosis and treatment.
Article
Most Colombian populations stem from the admixture of Caucasians, Amerindians and Negroids. In the world, these two latter ethnical groups show a significantly higher prevalence of epilepsy than the former one. We tested the hypothesis that the high prevalence of idiopathic epilepsy with generalized tonic clonic seizures found in the Antioquian population (Paisas), from Colombia, is due to their possible joint Negroid and Amerindian ethnic components. We have previously demonstrated that inheritance is the principal factor for developing epilepsy in this community. Analyses of racial admixture, heterogeneity between populations, genetic distance, and phyletic relationships were performed among epileptic and non epileptic samples from the Antioquian community. Also Caucasians, Spaniards, Basques, Jews, Chileans, Negroids, Amerindians and Mongoloids were included in the analysis. Four highly polymorphic blood systems were used as genetic markers: RH, MNS, ABO and FY. They were chosen because of their high discriminant power in these ethnic groups. In the population affected with idiopathic epilepsy, the estimated Negroid and Amerindian rates of admixture were low (3% and 14%, respectively). Although, these degrees of admixture can be explained due to common ancestral origins, the estimated proportion of Amerindian admixture in the epileptic affected population, was significantly higher than the estimated for the Non affected Antioquian population. The latter finding is consistent with the analysis of heterogeneity between populations that discriminated epileptic population from non epileptic Antioquian population (p < 0.05). Epileptic and non epileptic Paisas clustered in topology with Caucasians, very close to Spaniards and Basques and highly distant from Negroids and Amerindians. Thus, far, the origin of the high prevalence of idiopathic epilepsy in the Antioquian (Paisa) population cannot be explained by the hypothetical joint Negroid and Amerindian ethnical admixture, but using additional genetic markers and other methods of racial estimation of admixture it is necessary to corroborate if the Amerindian admixture component is significantly higher in the epileptic population than in the non epileptic Paisa population.
Article
The Virginia Twin Study of Adolescent Behavioral Development is a cohort-longitudinal epidemiological study that uses the genetic twin design to study the development and maintenance of child psychiatric disorders. We determined the rates of DSM-III-R disorders, disorders with impairment, and age, sex, and comorbidity effects. Families of 2762 white twins aged 8 to 16 years participated. Twins and their parents were asked systematically about risk factors and current psychiatric symptoms by means of investigator-based psychiatric interviews and questionnaires. The DSM-III-R diagnoses were made for major depressive disorder, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder. The 3-month point prevalence for any DSM-III-R disorders was 413 per 1000, and that for disorders with associated impairment was 142 per 1000. Emotional disorders with impairment occurred in 89 per 1000, with girls being more commonly affected; behavioral disorders had a prevalence of 71 per 1000, with boys being more frequently affected. The proportion with disorder who also had functional impairment varied across disorders; anxiety and phobic disorders were particularly likely not to be accompanied by impairment. Rates of emotional and behavioral disorders increased over the age range. There was extensive comorbidity among disorders. The prevalence rates and patterns of findings from this study of twins are consistent with those of other epidemiological studies, supporting previous findings of few differences in rates of psychiatric disorder between twins and singletons. The importance of including measures of functional impairment is evident by its effect on rates of disorder and patterns of comorbidity.
Article
We performed segregation analysis on 495 nuclear families, ascertained for the father's substance abuse diagnosis, in an attempt to determine the role of genetic and other influences in determining the variability of DSM-III-R-defined attention deficit hyperactivity disorder (ADHD). For our analyses, ADHD was treated as a quantitative variable, utilizing the semicontinuous scale provided by the 15-item symptom count within DSM-III-R. Analyses consisted of both class A and class D regressive models for which covariate effects (socioeconomic status) and sex dependence were estimated. Segregation analysis of the quantitative trait (ADHD symptom count) in the entire data set supported a transmissible non-Mendelian major effect. Models which were sex-dependent and included covariate effects provided the best fit to the data. In addition, similar analyses were performed on a 130-nuclear family subgroup of the data set in which at least one of the members of the nuclear family met DSM-III-R diagnostic criteria for ADHD. The sex-dependent Mendelian codominant model was best supported by the data, while other models could be rejected. Incorporating covariate effects did not provide a better fit for the data. Thus, this study is consistent with Mendelian transmission of ADHD symptom count in a clinically relevant population. Overall, our results support the presence of a heritable continuous trait of which ADHD represents an extreme.
Article
In order to elucidate the genetic and environmental components involved in the susceptibility to develop attention deficit hyperactivity disorder (ADHD), a complex segregation analysis on nuclear families (n = 53) ascertained from affected probands belonging to Medellín, in the Antioquian State, Colombia, was performed. Models of cohort effect (non-inheritance), multifactorial, recessive major gene, non-major gene component and non-transmission of major gene were rejected. Contrarily, dominant and codominant major gene models and non-multifactorial component could not be rejected. Thus, the better model fitting the data was that of the major gene (dominant/codominant). This major gene explains more than 99.99% of the ADHD phenotypic variance (value of heritability in the mixed model equal to 0.007%), which permit to assume a low aport of the environmental component to the phenotype ADHD. Gene frequency of the major gene was 3% in the general population of Antioquia and its penetrance was closed to 30%. Some cautions and aspects related to the bias of the interview and diagnosis of the parents are discussed.
Article
Converging evidence from family, twin, and adoption studies points to a substantial genetic component of the etiology of attention deficit hyperactivity disorder (ADHD). These data about ADHD have motivated molecular genetic studies of the disorder, which have produced intriguing but somewhat conflicting results. Some studies have reported associations with candidate genes and others not. Our review of the literature shows that one problem facing molecular genetic studies of ADHD is that its recurrence risk to first-degree relatives is only about five times higher than the population prevalence. This suggests that, to produce consistently replicated results, molecular genetic studies should either use much larger samples or should select those families in which genes exert the largest effect. Risch [(1990a) Am J Hum Genet 46:222-228; (1990b) Am J Hum Genet 46:229-241] proved that the statistical power of a linkage study increases with the magnitude of risk ratios (lambda's) computed by dividing the affection rate among each relative type to the rate of affection in the population. Our prior work suggests two dimensions of genetic heterogeneity that might be useful for selecting ADHD subjects for molecular genetic studies: comorbidity with conduct disorder and persistence of ADHD into adolescence. This paper shows that these sub-phenotypes are useful for molecular genetic studies because (1) they have much higher empirical lambda values and (2) they affect a substantial minority of ADHD patients.
Article
To describe the evolution of the Diagnostic Interview for Children and Adolescents (DICA) as well as the goals of the instrument and the issues surrounding its use. Administration procedures, psychometric properties, and comparisons with other measures are reviewed. The DICA, once considered a structured interview, can now be used in a semistructured format. It displays good reliability and works well with younger children. The DICA is a useful measure for both research and clinical settings, and it provides a reliable tool for assessing psychiatric information in children and adolescents.
Article
Symptom decline in attention deficit hyperactivity disorder (ADHD) was examined with different definitions of remission. Symptoms in 128 boys were measured five times over 4 years. The prevalences of syndromatic (less than full syndrome), symptomatic (less than subthreshold diagnosis), and functional (full recovery) remission were estimated as a function of age with multivariate logistic regression. Age was significantly associated with decline in total ADHD symptoms and symptoms of hyperactivity, impulsivity, and inattention. Symptoms of inattention remitted for fewer subjects than did symptoms of hyperactivity or impulsivity. The proportion of subjects experiencing remission varied considerably with the definition used (highest for syndromatic remission, lowest for functional remission). These results indicate that differences in reported remission rates reflect the definition used rather than the disorder's course. They provide systematic support for the clinical observation that hyperactivity and impulsivity symptoms tend to decline at a higher rate than inattention symptoms.
Article
Reports of possible genetic associations or linkages for attention deficit hyperactivity disorder are appearing at an increasing rate. As with many other neuropsychiatric disorders, claims of positive findings are frequently followed by negative reports. In this review, the evidence underpinning genetic hypotheses for the origins of ADHD is reviewed with particular emphasis on what is the heritable phenotype. It is concluded that advances in identifying mutations or allelic variations in genes predisposing to ADHD are likely, but the general replication of such findings must await a better characterization of the heritable phenotypic elements of ADHD and a better understanding of its genetic heterogeneity.
Article
Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.
Article
The assessment of attention deficit hyperactivity disorder (ADHD) in adults has been a source of controversy. The authors tested competing ideas by evaluating familial transmission among adult and nonadult relatives of ADHD children. They analyzed ADHD symptom data collected by structured interviews from the members of 280 ADHD and 242 non-ADHD families. For both past and current symptoms, both the boys' and girls' families showed significantly more familial aggregation for adult relatives than for nonadult relatives. The results were similar for inattentive and hyperactive-impulsive symptoms and for relatives with and without psychiatric comorbidity. The results provide further evidence for the validity of adult ADHD and support the intriguing idea that, from a familial perspective, the assessment of ADHD may be more valid in adults than in children. They do not support the idea that parents of ADHD children are biased to report ADHD symptoms in themselves because of their exposure to an ADHD child.
Article
We report the molecular characterization of three multiplex families and a sporadic case of juvenile Parkinsonism identified in the province of Antioquia (Colombia). Linkage and haplotype analysis using markers in 6q25.2-27 indicated that Parkinsonism in the pedigrees is linked to the parkin gene (maximum LOD-score of 3.85) but that they carry two different mutant haplotypes. Sequence analysis revealed a novel G to A transition in exon 6 at position 736 (G736A) of parkin. This change results in a non-conservative cysteine for tyrosine substitution. All affected individuals from two families were homozygous for this mutation, which was not detected in 100 normal controls. Patients from the family carrying the second haplotype and the sporadic case were homozygous for a GT insertion in exon 3. This mutation has been previously identified in French families with juvenile Parkinsonism. The concomitant presence of founder effects and allelic heterogeneity in Antioquia might relate to the founding admixture at the origin of this population.
Article
In the last years, it has been accumulated data about an important association between addictions and attention-deficit hyperactivity disorder (ADHD). Both disorders share clinic aspects and relevant biological markers, and for both it has been postulated alterations in the same cerebral systems. To evaluate the rate of possible ADHD in the early ages of adult alcoholic patients, in contrast with controls. It was realized an adaptation of Wender-Utah Rating Scale (WURS) and it was analyzed its psychometric characteristics. It was administered to 117 alcoholic patients and to 52 controls. The mean score of WURS is significatively higher in alcoholic group than in the control one (32.26 vs. 16.55, p< 0.0001). The percentage of alcoholic patients who has a score upper the different cut-off points (36 and 46) is also higher in alcoholic group than in the control one (36.75% vs 7.69%; p< 0.0005; 18.8% vs. 1.92%; p< 0.01, respectively). The mean score is higher in alcoholics with other comorbid addiction than in alcoholics without it (37.61 vs. 29.17; p< 0.018), and is higher in alcoholic patients who usually have intoxicated states in an high-moderate grade than those who have it in a low-nule one. Among alcoholic patients exists an important group with high scores in the WURS, it could indicate high rates of ADHD in early ages. It was discused the clinic and etiopathogenetics implications, and the convenience of advancing in the developemnt of diagnostic tools.
Article
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. To confirm clinically the prevalence of ADHD in Colombian children and adolescents. 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. 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%). A higher prevalence of ADHD was confirmed in Colombian population.
Article
Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.
Article
ADHD is a polygenic disorder due to the additive effect of genes affecting dopamine, norepinephrine, serotonin, GABA, and other neurotransmitters. Some of the specific loci involved are dopamine genes--DRD2, DRD4, DRD5, and the dopamine transporter; norepinephrine (NE) and epinephrine (EPI) genes--dopamine beta-hydroxylase, ADRA2A, ADRA2C, PNMT, norepinephrine transporter, MAOA, COMT; serotonin genes--TDO2, HTR1A, HTR1DA, serotonin transporter; GABA genes--GABRB3; androgen receptor and other genes. This model is consistent with all of the present knowledge about ADHD including (a) the increased frequency of ADHD in the relatives of ADHD probands, (b) the presence of a wide spectrum of comorbid behaviors (depression, anxiety, learning, conduct, oppositional-defiant, conduct and substance abuse disorders) in ADHD probands and their relatives on both parental sides, (c) the close relationship to Tourette syndrome (TS), (d) the failure to find the genes for TS using linkage analysis, (e) the brain imaging studies showing hypometabolism of the frontal lobes, (f) the relationship between dopamine D2 receptor density and regional blood flow, (g) the correlation between tics and dopamine D2 receptor density in TS, (h) the motor hyperactivity of dopamine transporter and dopamine D3 receptor gene knockout mice, (i) the LeMoal and Shaywitz dopamine deficiency animal models of ADHD, (j) the NE models of ADHD, (k) the failure to explain ADHD on the basis of any single neurotransmitter defect, (l) the response of ADHD to dopamine and alpha 2-adrenergic agonists, (m) the small percentage of the variance of specific behaviors accounted for by each gene, and numerous other aspects of ADHD. The implications of the polygenic model for the understanding, diagnosis and treatment of ADHD and TS, as well as other psychiatric disorders, are reviewed.
Article
Twin studies demonstrate the importance of genes and environment in the aetiology of childhood psychiatric and neurodevelopmental disorders. Advances in molecular genetics enable the identification of genes involved in complex disorders and enable the study of molecular mechanisms and gene--environment interactions. To review the role of molecular genetics studies in childhood behavioural and developmental traits. Molecular approaches to complex disorders are reviewed, with examples from autism, reading disability and attention-deficit hyperactivity disorder (ADHD). The most robust finding in ADHD is the association of a variable number tandem repeat polymorphism in exon 3 of the DRD4 gene. Other replicated associations with ADHD are outlined in the text. In autism, there is a replicated linkage finding on chromosome 7. Linkage studies in reading disability have confirmed a locus on chromosome 6 and strongly suggest one on chromosome 15. In the next 5--0 years susceptibility genes for these disorders will be established. Describing their relationship to biological and behavioural function will be a far greater challenge.