The main objective of this study was to examine neuropsychological mechanisms mediating the association between tryptophan hydroxylase 2 (TPH2) and attention deficit hyperactivity disorder (ADHD). A continuous performance test (T.O.V.A.) was administered to 344 participants diagnosed with DSM IV ADHD who were also genotyped for eight TPH2 intronic SNPs. Association between TPH2 (single SNPs and haplotypes), ADHD, and performance on the T.O.V.A. were tested using robust family-based association tests as implemented in two statistical genetic programs: UNPHASED and PBAT. Association was only observed between an eight locus haplotype and ADHD DSM IV combined type III (global P = 0.036). Robust association was observed between TPH2 single SNPs (and haplotypes) and performance on the T.O.V.A., especially Errors of Omission (eight locus haplotypes, global P = 0.038). Significant associations were also observed between TPH2 and improvement (before-after scores) in T.O.V.A. Total Response Variability scores following acute methylphenidate challenge (eight locus haplotypes, global P = 0.009). Using the MFBAT program, significant multivariate association was observed between single SNPs and haplotypes [eight locus haplotypes and all four T.O.V.A. variables (PBAT-GEE P = 0.013)]. The two most common TPH2 eight locus haplotypes were in a Yin Yang configuration and the Yang haplotype was the risk haplotype for both DSM IV ADHD and deficits in neuropsychological performance. The current investigation shows that risk for ADHD conferred by TPH2 variants is partially mediated by serotonergic mechanisms impacting some facets of executive function. Importantly, improvement in T.O.V.A. performance, especially on Response Time Variability, following methylphenidate was also associated with TPH2.
Copyright 2008 Wiley-Liss, Inc.