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. © 2015 Wiley Periodicals, Inc.

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.

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.

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.