Angélica Salatino-Oliveira

Genetics of attention-deficit/hyperactivity disorder: current findings and future directions

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting 5.29% of children worldwide. It presents a heterogeneous clinical expression, and both environmental and genetic factors are involved in the etiology. Despite high heritability estimates, identification of genes that confer susceptibility to ADHD has been a slow and difficult process. The first genetic studies targeted dopaminergic genes, but the effects were small and only explained a small portion of ADHD heritability. Recent studies focus on the identification of novel genes and pathways that may underlie ADHD. The main goal of this review is to present evidence from genome-wide association, copy number variation and family-based studies of genetic susceptibility to ADHD. The challenges involved to disclose ADHD susceptibility genes will be reviewed in order to provide directions for future studies.

Neural Mechanisms of Attention-Deficit/Hyperactivity Disorder Symptoms Are Stratified by MAOA Genotype

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in reward sensitivity and response inhibition. The relative contribution of these frontostriatal mechanisms to ADHD symptoms and their genetic determinants is largely unexplored. METHODS Using functional magnetic resonance imaging and genetic analysis of the monoamine oxidase A (MAOA) gene, we investigated how striatal and inferior frontal activation patterns contribute to ADHD symptoms depending on MAOA genotype in a sample of adolescent boys (n = 190). RESULTS We demonstrate an association of ADHD symptoms with distinct blood oxygen level-dependent (BOLD) responses depending on MAOA genotype. In A hemizygotes of the expression single nucleotide polymorphism rs12843268, which express lower levels of MAOA, ADHD symptoms are associated with lower ventral striatal BOLD response during the monetary incentive delay task and lower inferior frontal gyrus BOLD response during the stop signal task. In G hemizygotes, ADHD symptoms are associated with increased inferior frontal gyrus BOLD response during the stop signal task in the presence of increased ventral striatal BOLD response during the monetary incentive delay task. CONCLUSIONS Depending on MAOA genotype, ADHD symptoms in adolescent boys are associated with either reward deficiency or insufficient response inhibition. Apart from its mechanistic interest, our finding may aid in developing pharmacogenetic markers for ADHD.

Association of a carboxylesterase 1 polymorphism with appetite reduction in children and adolescents with attention-deficit/hyperactivity disorder treated with methylphenidate

Carboxylesterase 1 is the enzyme involved in methylphenidate (MPH) metabolism. The aim of this study was to evaluate the association between a −75 T>G polymorphism and appetite reduction in children with attention-deficit/hyperactivity disorder (ADHD). A sample of 213 children with ADHD was investigated. The primary outcome was appetite reduction measured by the Barkley Stimulant Side Effect Rating Scale applied at baseline, at 1 and 3 months of treatment. MPH doses were augmented until no further clinical improvement or significant adverse events occurred. The G allele presented a trend for association with appetite reduction scores (P=0.05). A significant interaction between the G allele and treatment over time for appetite reduction scores was also observed (P=0.03). The G allele carriers presented a higher risk for appetite reduction worsening when compared with T allele homozygotes (odds ratio=3.47, P=0.01). The present results suggest an influence of carboxylesterase 1 −75 T>G polymorphism on the worsening of appetite reduction with MPH treatment in youths with ADHD.

ADHD pharmacogenetics across the life cycle: New findings and perspectives

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.

Catechol-O-Methyltransferase Valine158Methionine Polymorphism Moderates Methylphenidate Effects on Oppositional Symptoms in Boys with Attention-Deficit/Hyperactivity Disorder

BACKGROUND The catechol-O-methyltransferase enzyme plays a key role in the function of prefrontal cortex, accounting for most of the degradation of dopamine. Previous studies have documented the improvement of oppositional symptoms in attention-deficit/hyperactivity disorder (ADHD) patients with methylphenidate (MPH) treatment. However, the effect of the COMT gene in the response to MPH on oppositional symptoms has not been investigated. METHODS A total of 251 children with ADHD fulfilled inclusion criteria to participate in the study. Dosages of short-acting MPH were augmented until no further clinical improvement was detected or until there were significant adverse events (MPH dose always > .3 mg/kg/day). The outcome measure was the parent-rated oppositional subscale of the Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV). The scale was applied by child psychiatrists blinded to genotype at baseline and in the first and third months. The COMT valine158methionine polymorphism was genotyped by polymerase chain reaction based methods. RESULTS We detected significant improvement in SNAP-IV oppositional scores from baseline to the first and three months of treatment [n = 112; F(2,231) = 5.35, p = .005]. A significant effect of the presence of methionine allele in oppositional defiant disorder scores during treatment [F(1,148) = 5.02, p = .027] and a significant interaction between the methionine allele and treatment over time for the SNAP-IV oppositional scores during this period of treatment [F(2,229) = 6.40, p = .002] were both observed. CONCLUSIONS These results suggest an effect of the COMT genotype on the trajectory of oppositional defiant disorder symptoms improvement with MPH treatment in boys with ADHD.

G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics

AIMS Clozapine treatment of schizophrenia is effective only in 30-60% of individuals. Since genetic factors are believed to play a significant role in the variation of response to antipsychotics, the aim of the present study was to verify the effect of a G-protein gene polymorphism on clozapine response and clozapine-induced generalized seizures in Brazilian patients with schizophrenia. PATIENTS & METHODS In total, 121 schizophrenic patients in treatment with clozapine were genotyped for the 825C>T polymorphism it the GNB3 gene using PCR. RESULTS Homozygosity for the T825 allele was more frequent among nonresponders (chi(2) = 7.708; p = 0.021), and carriers of this allele had a higher risk to present a convulsion episode (chi(2) = 7.279; p = 0.007). These results were confirmed after controlling for covariates by logistic regression. CONCLUSION Our data suggest an influence of the 825C>T polymorphism on clozapine response in persons with schizophrenia and also on a specific neurological side effect (generalized seizures) under clozapine treatment.

Cadherin‐13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder

Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P‐value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P‐value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD.

LPHN3 and attention-deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study.

Latrophilin 3 (LPHN3) is a brain‐specific member of the G‐protein coupled receptor family associated to both attention‐deficit/hyperactivity disorder (ADHD) genetic susceptibility and methylphenidate (MPH) pharmacogenetics. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of this study was to evaluate the role of LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetic study, 172 children with ADHD were investigated. The primary outcome measure was the parent‐rated Swanson, Nolan and Pelham Scale – version IV applied at baseline, first and third months of treatment with MPH. The results reported herein suggest the CGC haplotype derived from single nucleotide polymorphisms (SNPs) rs6813183, rs1355368 and rs734644 as an ADHD risk haplotype (P = 0.02, OR = 1.46). Although non‐significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (P = 0.03, OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a nominally significant interaction with treatment over time (P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD.

Gene-Environment Interaction in Youth Depression: Replication of the 5-HTTLPR Moderation in a Diverse Setting

OBJECTIVE Replication of scientific findings is a major challenge in biomedical research. In psychiatry, the identification of measured gene-environment interactions (G×E) has promoted a heated debate over the past decade, with controversial results about its influence on disorders such as major depression. The authors sought to replicate a 2003 study on G×E in youth depression in a large birth cohort from a diverse setting. METHOD Using data from the 1993 Pelotas Birth Cohort Study, and adopting a design as similar as possible to that of the original study, the authors tested whether the relationship between childhood maltreatment and a subsequent depressive episode diagnosis was moderated by 5-HTTLPR genotype. Of 5,249 individuals assessed at birth and followed up to age 18, data on the evaluation for depressive episodes in early adulthood, on childhood maltreatment, and on genotype were available for 3,558 participants, of whom 2,392 remained after conservative screening for previous depressive symptoms. Associations were investigated with logistic regression analyses and controlling for potential confounders. RESULTS The results replicated important findings of the original study, this time in a sample of young adults from a middle-income country: there was a differential dose-response relationship between childhood maltreatment and major depression according to 5-HTTLPR genotype. CONCLUSIONS After following a research strategy as comparable as possible to that of the original study, the results corroborated the existence of a measured G×E, now in a large sample from a different sociocultural context. These findings provide further evidence that a genetic variant in the 5-HTTLPR moderates the link between childhood maltreatment and youth depression.

Glutamatergic copy number variants and their role in attention-deficit/hyperactivity disorder.

Attention‐Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762–1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066–3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631–9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals.