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

Abstract

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.

Attention-deficit hyperactivity disorder in adults: A systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies

“…A summary of genetic studies of adult ADHD was reported in Franke et al 32 in a comprehensive review. The literature about adult ADHD now comprises six meta-analyses of candidate genes in International multi-center persistent ADHD collaboration (IMpACT) samples, 33, 34, 35, 36, 37, 38 two SNP-GWAS, 39, 40 two CNV-GWAS 41, 42 studies and three reviews of pharmacogenetics studies. 30, 43, 44 No meta-analyses of biochemical studies of adult ADHD have been reported.…”

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

“…Marked neurodevelopmental influences of genomic imprinting set the stage for structural-physiological variation that affect cognition, emotion, and pathophysiology of ADHD (e.g., [24]). Nevertheless, although innumerable gene association studies have provided a huge amount of evidence for multi-involvement for neurotransmitters and metabolic enzymes (e.g., monoamine oxidase [MAO] or tryptophan hydroxylase [TPH]) in genetic predispositions for the disorder, the conflicting results, due to failure to obtain association, are rife [25–27]. …”

Pilot study: potential transcription markers for adult attention-deficit hyperactivity disorder in whole blood

“…The most consistent evidence for an association with ADHD exists for the DRD5 gene microsatellite (Squassina et al 2008) and the SLC6A3 gene variable tandem repeat (VNTR) at the 3 0 UTR (Stergiakouli and Thapar 2010;Gizer et al 2009). In contrast, very weak individual associations were reported for TPH1 (Gizer et al 2009;Johansson et al 2010) and SNAP25 (Gizer et al 2009;Forero et al 2009;Kim et al 2007), but the 3 0 UTR of the latter was significant in a recent meta-analysis (Gizer et al 2009). Each of these genes often showed a (Gizer et al 2009).…”