No causal role for the G482T and G689T polymorphisms in translation regulation of serotonin transporter (SLC6A4) or association with attention-deficit-hyperactivity disorder (ADHD)

Purpose of the study: The G482T and G689T polymorphisms in the 3′-UTR of serotonin transporter (SLC6A4) are implicated in translational regulation and allelic variants may mediate susceptibility to attention-deficit-hyperactivity disorder (ADHD). Accordingly, we examined influence of allelic variation on stable secondary structure formation and on seed sequences necessary for microRNA-binding. Furthermore, 90 ADHD cases from India were genotyped for these markers and tested for association with ADHD. Methods: The Mfold software was used for secondary structure predictions and miRNA-binding sequences were obtained from the PicTar database. Using a family-based study design we assessed genetic association by means of the haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. With respect to G689T, previously published TDT data were included in pooled analysis. Result: Secondary structure analysis reveals that G482, U482, G689 and U689 conformers are energetically similar. Unlike G482, the U482 change maps within a loop and this conformer differs in free energy by ∼4.4 kcal/mol. While G482T is proximal to various miRNA-binding sequences, it is not part of the seed sequence for any of them. Thus, G482T and G689T polymorphisms do not regulate SLC6A4 translation in cis. From the HHRR (χ2 = 0.860, p = 0.353; R.R. = 1.11; 95% C.I. = 0.89–1.65 for G482T; χ2 = 0.902, p = 0.342; R.R. = 1.17; 95% C.I. = 0.83–1.32 for G689T), TDT (χ2 = 1.33, p = 0.25; O.R. = 1.35; 95% C.I. = 0.94–1.94 for G482T; χ2 = 1.45, p = 0.23; O.R. = 1.44; 95% C.I. = 0.94–2.22 for G689T) and pooled TDT (χ2 = 0.52, p = 0.47; O.R. = 1.05; 95% C.I. = 0.96–1.15) statistics we infer that these polymorphisms are not associated with risk of ADHD.