Claiton Henrique Dotto Bau

The genetics of attention deficit/hyperactivity disorder in adults, a review

The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.

Y-Chromosome Evidence for Differing Ancient Demographic Histories in the Americas

To scrutinize the male ancestry of extant Native American populations, we examined eight biallelic and six microsatellite polymorphisms from the nonrecombining portion of the Y chromosome, in 438 individuals from 24 Native American populations (1 Na Dené and 23 South Amerinds) and in 404 Mongolians. One of the biallelic markers typed is a recently identified mutation (M242) characterizing a novel founder Native American haplogroup. The distribution, relatedness, and diversity of Y lineages in Native Americans indicate a differentiated male ancestry for populations from North and South America, strongly supporting a diverse demographic history for populations from these areas. These data are consistent with the occurrence of two major male migrations from southern/central Siberia to the Americas (with the second migration being restricted to North America) and a shared ancestry in central Asia for some of the initial migrants to Europe and the Americas. The microsatellite diversity and distribution of a Y lineage specific to South America (Q-M19) indicates that certain Amerind populations have been isolated since the initial colonization of the region, suggesting an early onset for tribalization of Native Americans. Age estimates based on Y-chromosome microsatellite diversity place the initial settlement of the American continent at approximately 14,000 years ago, in relative agreement with the age of well-established archaeological evidence.

The TaqI A1 allele of the dopamine D2 receptor gene and alcoholism in Brazil: Association and interaction with stress and harm avoidance on severity prediction

Allele and genotype frequencies of the TaqI A polymorphism of dopamine D2 receptor (DRD2) gene were compared in 115 alcohol-dependent Brazilian males and 114 ethnically matched controls. Regression analyses were performed to test for an interactive effect between the DRD2 TaqI A1 allele and measures of stress and harm avoidance on severity of alcoholism and number of antisocial personality symptoms. A slightly positive association of DRD2 TaqI A1 genotypes with alcoholism was observed, by standard and molecular heterosis approaches. The DRD2 TaqI A1 allele showed significant interaction with stress and harm avoidance in predicting the severity of physiologic dependence, and with harm avoidance for the number of antisocial personality symptoms. Separate partial correlation analyses showed that stress-related variables were significantly correlated with severity scores in alcoholics with the allele, but not in those without it. This is the first demonstration of an interaction between a genetic polymorphism and stress-related measures on the severity of psychiatric disorders.

MAOA-uVNTR polymorphism in a Brazilian sample: further support for the association with impulsive behaviors and alcohol dependence.

The enzyme monoamine oxidase A (MAO A) plays an important role in the metabolism of neurotransmitters. The MAOA gene presents several polymorphisms, including a 30‐bp VNTR in the promoter region (MAOA‐uVNTR). Alleles with 3.5 and 4 repeats are 2–10 times more efficient than the 3‐repeat allele. Several studies have shown an association between the 3‐repeat allele and a cluster of externalizing behaviors including alcoholism, antisocial personality, and impulsivity. The objective of the present study is to replicate in a different culture the associations between the MAOA‐uVNTR with alcoholism and other phenotypes. The sample comprises 125 Brazilian alcoholics of European descent and 235 controls. The results suggest that the 3‐repeat allele is associated to: (1) alcohol dependence (P < 0.05); (2) an earlier onset of alcoholism (P < 0.01); (3) comorbid drug abuse among alcoholics (P < 0.05); and (4) a higher number of antisocial symptoms (P < 0.02). Our results confirmed previous reports showing an association of the low activity 3‐repeat allele of MAOA‐uVNTR polymorphism with substance dependence and impulsive/antisocial behaviors. These findings in a different culture further support the influence of the MAOA‐uVNTR in psychiatric disorders.

Lack of gender effects on subtype outcomes in adults with attention-deficit/hyperactivity disorder : Support for the validity of subtypes

The aim of the present study is to verify if gender modifies the clinical, adaptative and psychological outcomes of adult attention–deficit/hyperactivity disorder (ADHD) subtypes. We evaluated 219 clinically referred adult patients. The interviews followed the DSM–IV criteria,using the K–SADS–E for ADHD and oppositional defiant disorder and SCID–IV for comorbidities. Regression models were used to analyze gender and subtype main effects and interactions in psychiatric outcomes. In the initial sample, 117 patients (53.5%) were of the combined subtype, 88 (40%) were inattentives and 14 (6.5%) hyperactives. There were no significant interactions between gender and subtype in any variable assessed. Men and women did not differ in the relative frequency of each subtype. Patients of the combined subtype in both genders presented a higher severity and increased rates of conduct and ODD disorders than inattentives. The main effects of gender and subtype in this sample are similar to those previously reported in other countries, suggesting the cross–cultural equivalence of the phenotype. The absence of significant interactions between gender and subtype suggests that, at least in clinical–based samples, DSM–IV adult ADHD subtypes present cross–gender validity.

Late-onset ADHD in adults: Milder, but still dysfunctional

OBJECTIVE The requirement in classificatory systems that some impairment from attention-deficit/hyperactivity disorder (ADHD) symptoms starts before 7 years of age (age of onset of impairment criteria - AOC) has been harshly criticized. Although there is evidence that late-onset ADHD is a valid diagnosis, little is known about the role of age of onset of impairment on the clinical profile of adult patients. METHODS The diagnoses of 349 adults with ADHD followed DSM-IV criteria. ADHD and oppositional defiant disorder (ODD) were evaluated with the K-SADS-E, and other comorbidities with the SCID-IV and the MINI. Subjects were divided in early and late-onset groups (age of onset of impairment between 7 and 12 years old). The effect of age of onset over clinical and demographic characteristics was tested by regression models. RESULTS Late-onset subjects were diagnosed later (P=0.04), had a lower frequency of problems with authority and discipline (P=0.004), and lower scores in SNAP-IV (P<0.001) and in Barkleys scale for problems in areas of life activities (P=0.03). On the other hand, late-onset patients presented a higher prevalence of comorbid general anxiety disorder (GAD) (P=0.01). Both groups had a similar profile in the remaining comorbidities and sociodemographic characteristics. CONCLUSIONS This study provides initial evidence that adults with late-onset ADHD have less severity, lower frequency of externalizing symptoms and increased comorbidity with GAD, but similar profile in other comorbidities. In addition, the data suggest that late-onset patients have a higher probability of delayed diagnosis despite the significant impairment of their condition.

Y-chromosome biallelic polymorphisms and Native American population structure

It has been proposed that women had a higher migration rate than men throughout human evolutionary history. However, in a recent study of South American natives using mtDNA restriction fragment polymorphisms and Y-chromosome microsatellites we failed to detect a significant difference in estimates of migration rates between the sexes. As the high mutation rate of microsatellites might affect estimates of population structure, we now examine biallelic polymorphisms in both mtDNA and the Y-chromosome. Analyses of these markers in Amerinds from North, Central and South America agree with our previous findings in not supporting a higher migration rate for women in these populations. Furthermore, they underline the importance of genetic drift in the evolution of Amerinds and suggest the existence of a North to South gradient of increasing drift in the Americas.

DRD4 and DAT1 as modifying genes in alcoholism: interaction with novelty seeking on level of alcohol consumption

DRD4 and DAT1 as modifying genes in alcoholism: interaction with novelty seeking on level of alcohol consumption

Dopamine D4 receptor gene and personality dimensions in Brazilian male alcoholics.

The presence of the seven-repeat allele of the VNTR in the exon 3 of the dopamine D4 receptor gene (DRD4) has been associated in healthy subjects to the personality trait of novelty seeking. The present study focuses these observations on a sample of Brazilian male alcoholics, evaluated on the temperament dimensions originally described by Cloninger. The genotypes observed are in agreement with those expected under Hardy-Weinberg equilibrium. Subjects with the seven-repeat allele manifest lower harm avoidance scores. No significant differences between subjects with or without the seven-repeat allele in the scores of novelty seeking or reward dependence were observed. The lack of association between novelty seeking and the DRD4 exon 3 polymorphism is further corroborated by the fact that the comorbid antisocial personality disorder is not associated to the presence of the seven-repeat allele. These results could be explained by a biological connection between the personality dimensions of novelty seeking and harm avoidance.

Inattention and Hyperactivity Dimensions of ADHD Are Associated with Different Personality Profiles

Background: Previous studies have suggested that individuals with ADHD have high scores in novelty seeking and harm avoidance. However, it is not known whether personality is associated with specific subtypes and dimensions of the disorder. The aim of this study is to test for associations between scores in the temperament and character inventory of C.R. Cloninger with adult ADHD subtypes and severity. Sampling and Methods: The diagnostic interviews of 296 adult ADHD patients followed the DSM-IV criteria. ADHD dimensions were evaluated with the SNAP-IV scores, and personality dimensions were assessed using the Temperament and Character Inventory. Results: The combined subtype (n = 168) was associated with higher scores in novelty seeking (p < 0.001) and lower scores in cooperativeness (p = 0.006) than the inattentive subtype (n = 128). Higher inattention scores were associated with decreased self-directedness (p < 0.001) and increased harm avoidance (p = 0.02), whereas higher hyperactivity/impulsivity scores correlated positively with novelty seeking (p < 0.001) and persistence (p = 0.03). Conclusions: These findings suggest that personality dimensions are strongly correlated with ADHD subtypes and severity dimensions, pointing to the need for studies evaluating the mechanisms behind this association.