E.T. Landaas

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4–5% in children and 1–4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3′-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3′-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Genetic Analyses of Dopamine Related Genes in Adult ADHD Patients Suggest an Association With the DRD5-Microsatellite Repeat, But Not With DRD4 or SLC6A3 VNTRs

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta‐analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3′UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148‐bp allele consistent with recent meta‐analyses. The strongest overall association (P = 0.02) and increased risk for the 148‐bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00–1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long‐term clinical outcome.

An international multicenter association study of the serotonin transporter gene in persistent ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5‐HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta‐analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5‐HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta‐analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67–1.09; P = 0.20]. For 5‐HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta‐analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00–1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5‐HTTLPR and a role for rare variants cannot be excluded.

The impact of cyclothymic temperament in adult ADHD

BACKGROUND Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder in children and adults. Many ADHD patients experience affective symptoms that resemble the cyclothymic temperament trait, which is suggested to be a part of the bipolar spectrum. However, the relationship between adult ADHD and cyclothymic temperament has never been systematically studied. METHODS A sample of 586 clinically diagnosed Norwegian adult ADHD patients and 721 population derived controls responded to the 21-item cyclothymic subscale of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego auto-questionnaire (TEMPS-A). Self-reported data on psychiatric symptoms, comorbidity, educational and occupational level, and known comorbidity in family members, including bipolar disorder, was also obtained. RESULTS The mean TEMPS-A scores were 13.0 for patients and 4.6 for controls (p<0.001), and 71% of the patients compared to 13% of the controls were classified as having a cyclothymic temperament (TEMPS score ≥11 points). Among ADHD patients, cyclothymic temperament was strongly associated with more childhood and adult ADHD symptoms, lower educational and occupational achievements and increased psychiatric comorbidity, including bipolar disorder (10%). In addition, 49% screened positive on the Mood Disorder Questionnaire. LIMITATIONS Although the cyclothymic TEMPS-A scale has been used in clinical settings in Norway for many years, it has not yet been officially validated. CONCLUSIONS Cyclothymic temperament is highly prevalent in adults with ADHD, and this characterises a subgroup of more psychiatrically impaired individuals, possibly reflecting an underlying affective instability with a pathophysiology closer to the bipolar spectrum disorders.

Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: a meta-analysis in four European populations

Attention‐deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4–8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single‐marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple‐marker meta‐analysis showed a nominal association (P = 0.02) of the L‐4R haplotype (dup120bp‐48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R‐6R haplotype (3′UTR VNTR‐intron 8 VNTR) in the same dataset, we further tested for gene × gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.

Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations†

The tryptophan hydroxylase 1 and 2 (TPH1 and TPH2) genes encode the rate‐limiting enzymes in the serotonin biosynthesis. Genetic variants in both genes have been implicated in several psychiatric disorders. For attention‐deficit/hyperactivity disorder (ADHD) in children, the results are conflicting, and little is known about their role in adult ADHD patients. We therefore first genotype‐tagged all common variants within both genes in a Norwegian sample of 451 patients with a diagnosis of adult ADHD and 584 controls. Six of the single nucleotide polymorphisms (SNPs) were subsequently genotyped in three additional independent European Caucasian samples of adult ADHD cases and controls from the International Multicenter persistent ADHD Collaboration (IMpACT). None of the SNPs reached formal study‐wide significance in the total meta‐analysis sample of 1,636 cases and 1,923 controls, despite having a power of >80% to detect a variant conferring an OR = 1.25 at P = 0.001 level. Only the TPH1 SNP rs17794760 showed nominal significance [OR = 0.84 (0.71–1.00), P = 0.05]. In conclusion, in the single largest ADHD genetic study of TPH1 and TPH2 variants presented to date (n = 3,559 individuals), we did not find consistent evidence for a substantial effect of common genetic variants on persistent ADHD.

Bipolar disorder risk alleles in adult ADHD patients

Attention‐deficit/hyperactivity disorder (ADHD) has an estimated prevalence of 3–5% in adults. Genome‐wide association (GWA) studies have not been performed in adults with ADHD and studies in children have so far been inconclusive, possibly because of the small sample sizes. Larger GWA studies have been performed on bipolar disorder (BD) and BD symptoms, and several potential risk genes have been reported. ADHD and BD share many clinical features and comorbidity between these two disorders is common. We therefore wanted to examine whether the reported BD genetic variants in CACNA1C, ANK3, MYO5B, TSPAN8 and ZNF804A loci are associated with ADHD or with scores on the Mood Disorder Questionnaire (MDQ), a commonly used screening instrument for bipolar spectrum disorders. We studied 561 adult Norwegian ADHD patients and 711 controls from the general population. No significant associations or trends were found between any of the single nucleotide polymorphisms (SNPs) studied and ADHD [odds ratios (ORs) ≤ 1.05]. However, a weak association was found between rs1344706 in ZNF804A (OR = 1.25; P = 0.05) and MDQ. In conclusion, it seems unlikely that these six SNPs with strong evidence of association in BD GWA studies are shared risk variants between ADHD and BD.

No association between the serotonin transporter gene polymorphism 5-HTTLPR and cyclothymic temperament as measured by TEMPS-A

BACKGROUND Temperaments are stable personality traits that can be considered subsyndromal risk factors of psychiatric illnesses. The 5-HTTLPR polymorphism of the serotonin transporter gene has been found to be associated with affective temperaments, particularly the cyclothymic temperament, as measured with the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A). In this study we have attempted to replicate this finding in a population-based sample which is five times as large as the sample used in the original study. METHODS The 21 items of the cyclothymic subscale of TEMPS-A was filled in by 691 individuals (404 females, 287 males, 18-40 years) randomly recruited from the general population. DNA was isolated from saliva, and the serotonin transporter polymorphism 5-HTTLPR was genotyped using the polymerase chain reaction and fragment analysis. RESULTS No significant association was found between 5-HTTLPR genotype and TEMPS-A score, neither when analysing by an additive allelic model nor when the different genotypes and allelic dominance were examined. Furthermore, no association was observed after gender stratification, or when TEMPS-A was analysed as a dichotomous measure, using a cut-off of ≥11 positive item responses. LIMITATIONS Although being used in clinical settings, TEMPS-A has not been officially validated in Norway. CONCLUSIONS This study suggests that there is no association between the 5-HTTLPR polymorphism and cyclothymic temperament as measured by TEMPS-A.

On the Role of NOS1 ex1f-VNTR in ADHD—Allelic, Subgroup, and Meta-Analysis

Attention deficit/ hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co‐morbidity analysis. Our previous finding held true in the extended sample, and also meta‐analysis demonstrated an association of NOS1 ex1f‐VNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the 21‐repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the 21‐repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post‐mortem brain samples. These data validate the role of NOS‐I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association.

Vitamin levels in adults with ADHD

Background Micronutrients containing vitamins are reported to reduce symptom levels in persons with attention-deficit hyperactivity disorder (ADHD), but data on vitamin levels in ADHD are sparse. Aims To examine the relationship between vitamin concentrations, ADHD diagnosis and psychiatric symptoms in young adult ADHD patients and controls. Method Eight vitamins and the nicotine metabolite cotinine were analysed in serum samples from 133 ADHD patients and 131 controls aged between 18 and 40, who also reported ADHD symptoms and comorbid conditions. Results Lower concentrations of vitamins B2, B6 and B9 were associated with the ADHD diagnosis, and B2 and B6 also with symptom severity. Smokers had lower levels of vitamins B2 and B9. Conclusions ADHD patients were overrepresented in the group with low levels of some vitamins, possibly indicative of inadequate dietary intake of these micronutrients in a subgroup of patients. It is important to identify these patients in dietary intervention trials of ADHD. Declaration of interest J.H. has received lecture honoraria as part of continuing medical education programmes sponsored by Novartis, Eli Lilly and Company, and Janssen-Cilag. Copyright and usage