Although the result of a double-blind placebo-controlled crossover study indicated a possible effect of BH4 treatment in children with autistic disorder (Danfors, T. et al, 2005
), our previous studies showed only modest association to autism for the genes in the dopamine and serotonin pathways (Anderson, B.M. et al, 2008
; Anderson, B.M. et al, 2009
). In the dopamine pathway study, however, we found that YWHAB
(tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide), the activation protein for tyrosine-3-hydroxylase (TH
), has a nominal association to the disorder. TH
uses BH4 as a cofactor to metabolize tyrosine into L-DOPA, the precursor of dopamine. The results from this present study were modest, revealing only a marginal association with PTS
, one of the genes responsible for BH4’s biosynthesis. However, this association did not withstand the correction for multiple testing and was not replicated in the GWAS dataset.
When the hypothesis that gene-gene interaction might play an important role in the disease was tested using MDR, a modest association was detected between PTS and SPR in a 2-way interaction model in the overall dataset. Given that PTS and SPR are two consecutive genes in the BH4 synthesis (), the fact that they show epistasis may require further investigation. Using the data from our previous studies of the dopamine and serotonin pathways, we ran MDR on the 3 pathways combined, but no gene-gene interaction was detected.
The underlying assumption that common variations in these genes are responsible for modulating the risk of autism also had an impact on our analysis. Even though we captured a significant number of these variations, our study was not fully comprehensive. Furthermore, Weiss et al. have hypothesized that rare variations (de novo mutation, deletions, duplications, point mutations) present in a large number of genes could account for as much as 90% of idiopathic autism (Weiss, L.A. et al, 2008
). If true, this would indicate that our study might not have enough power to overcome the locus heterogeneity to detect rare variations. Given that such alternatives would significantly impact the power of the PDT and MDR analysis, our data nevertheless suggest at least a modest role for one BH4-related gene (PTS
) in the risk of developing autism.