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


RESULTS
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 approximately 4.4kcal/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 (chi(2)=0.860, p=0.353; R.R.=1.11; 95% C.I.=0.89-1.65 for G482T; chi(2)=0.902, p=0.342; R.R.=1.17; 95% C.I.=0.83-1.32 for G689T), TDT (chi(2)=1.33, p=0.25; O.R.=1.35; 95% C.I.=0.94-1.94 for G482T; chi(2)=1.45, p=0.23; O.R.=1.44; 95% C.I.=0.94-2.22 for G689T) and pooled TDT (chi(2)=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.
Manovikas Biomedical Research & Diagnostic Centre, 482 Madudah, Plot I-24, Sector-J, Eastern Metropolitan Bypass, Kolkata 700107, India.
Emili
E
Banerjee
Swagata
S
Sinha
Anindita
A
Chatterjee
Krishnadas
K
Nandagopal
D020413:3' Untranslated Regions / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D017433:Protein Structure, Secondary; D012307:Risk Factors; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics*
D020413:3' Untranslated Regions; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins