Recent discoveries on genetic factors related to Attention - Deficit / Hyperactivity Disorder (ADHD)
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral childhood condition with neurological and genetic basis [Purper-Ouaki et al, 2010]. Its behavioral and cognitive symptoms, such as lack of concentration, difficulties with self control, impulsiveness, and motor hyperactivity, often have a negative impact in the child’s social development and ability [Stergiakouli et al, 2010]. These symptoms often persist into adulthood [Purper-Ouaki et al, 2010].
Genetic factors are part of ADHD’s multifactorial, heterogeneous etiology [Purper-Ouaki et al, 2010]. Studies with monozygotic and dizygotic twins pairs, and adopted siblings have shown that ADHD is highly heritable (0.76) [Thakur et al, 2010; Stergiakouli et al, 2010].
This paper presents some of the most recent research findings related to some of the genetic factors affecting Attention-Deficit / Hyperactivity Disorder (ADHD) and its treatment.
Relationship between a SLC6A4 gene polymorphism and response to methylphenidate (MPH) in ADHD patients [Thakur et al, 2010]
The purpose of this study [Thakur et al, 2010] was to investigate the relationship, if any, between a polymorphism in the SLC6A4 gene and the patient’s behavioral responses to methylphenidate. SLC6A4 is the gene that encodes the serotonin transporter protein.
Methylphenidate (MPH) can reduce ADHD symptoms in children by as much as 70% [Kim et al, 2010]. Methylphenidate is believed to work by modulating dopamine and serotonin transmission in the patient’s brain [Thakur et al, 2010].
In the SLC6A4 gene’s promoter region, the polymorphism is composed of three alleles: s (short), lA (long A) and lG (long G) [Thakur et al, 2010]. Since alleles s and lG were determined to be associated with a low transcription level of the gene, they were considered as equivalent [Thakur et al, 2010]. The study therefore used the following genotypes: s’s’ (composed of alleles ss, lG lG , and s lG), s’l’ (composed of alleles lA lG , and s lA), and l’l’ (composed of alleles lA lA).
The triallelic polymorphism of the promoter region of SLC6A4, the serotonin transporter gene, has a significant effect on the patient’s response to methylphenidate (MPH). Those patients who are homozygous for the “long” allele (l’l’ genotype) respond better to methylphenidate than patients who are homozygous for the “short” allele (s’s’ genotype) [Thakur et al, 2010].
ADHD patients were treated with 0.5 mg per kg per day of methylphenidate, or with placebo. Their behavior was evaluated at the start of treatment (baseline) and after each week of treatment using Conner’s Global Index (CGI) for parents and teachers. The patients were genotyped to determine their genotype groups for this gene, and their DNA was amplified using Polymerase Chain Reaction (PCR). The different alleles were then separated using agarose gel electrophoresis.
A mixed-mode ANOVA (Analysis of Variance) statistical analysis was used to determine any statistically significant interactions between genotype, treatment, and genotype/ treatment interactions [Thakur et al, 2010].
The study found that the effect of methylphenidate treatment varies according to the patient’s SLC6A4 genotype. Patients with the l’l’ genotype showed a statistically significant improvement in behavior when using methylphenidate, and a minimal response to placebo; while those with the s’s’ genotype showed better responses to placebo than to methylphenidate. An intermediate level of response was observed in patients with the s’l’ genotype when compared to l’l’ and s’s’ patients.
The hypothesis, that the triallelic polymorphism of the SLC6A4 gene’s promoter region has a significant effect on the patient’s response to methylphenidate treatment, was not rejected. Methylphenidate had a greater effect in the behavior l’l’ genotype ADHD patients, and lower effect in s’l’ genotype ADHD patients. Methylphenidate did not have a significant effect in improving symptoms of s’s’ genotype ADHD patients.
Relationship between two SLC6A2 gene polymorphisms, and response to methylphenidate (MPH) in ADHD patients [Kim et al, 2010]
The purpose of this study [Kim et al, 2010] was to investigate the relationship, if any, of two specific polymorphisms of SLC6A2, the gene that encodes the norepinephrine transporter protein, with behavioral responses to methylphenidate in children and adolescents. The -3081 (A/T) polymorphism consists of a single nucleotide change, from A to T, in the SLC6A2 gene’s promoter region [Kim et al, 2010]. The G1287A polymorphism also consists of a single nucleotide change, at exon 9 of the gene [Kim et al, 2010].
The -3081(A/T) and G1287A polymorphisms of the norepinephrine transporter gene SLC6A2 have a significant effect on the response to methylphenidate treatment in ADHD patients [Kim et al, 2010].
The behavior of ADHD patients taking periodically-adjusted doses of methylphenidate was evaluated using the Clinical Global Impression Improvement (CGI-I) scale. Patients were also evaluated using the ADHD Rating Scale IV (ARS). Patients were evaluated by psychiatrists prior to medication, medicated with methylphenidate during eight weeks, and evaluated by psychiatrists again to determine the effectiveness, if any, of the treatment [Kim et al, 2010].
Genomic DNA samples were taken from the patients in order to determine their genotypes; DNA was amplified using Polymerase Chain Reaction (PCR). An estimation of allele frequencies was obtained for the genotypes of all patients. A Hardy-Weinberg equilibrium for genotype and allele frequencies was performed using a goodness-of-fit c2 test. The correlation between the changes in ARS scores after treatment with methylphenidate, and the subjects’ SLC6A2 genotype, was evaluated using a one-way ANOVA statistical analysis, and a t-test hypothesis test [Kim et al, 2010].
For the -3081 polymorphism, the study found that methylphenidate treatment had a significant effect on ADHD symptoms on subjects homozygous or heterozygous for the T allele (T/T or A/T genotypes). These subjects showed a measurable improvement in their ADHD symptoms after treatment with methylphenidate.
The study did not detect any association between methylphenidate treatment for ADHD symptoms and the G1287A polymorphism genotypes.
The hypothesis that -3081(A/T) polymorphisms of the norepinephrine transporter gene SLC6A2 is involved in the subjects’ response to methylphenidate treatment was not rejected. Experimental results showed evidence that methylphenidate treatment had a significant effect on patients homozygous or heterozygous for the T allele.
The hypothesis that G1287A polymorphisms of the norepinephrine transporter gene SLC6A2 have a significant effect on the subjects’response to methylphenidate was rejected. No such effect was observed.
1. Kim et al.: Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. Behavioral and Brain Functions 2010; 6:57.
2. Purper-Ouaki et al.: Neurobiology of attention deficit/hyperactivity disorder. Med Sci (Paris). 2010 May; 26(5): 487-496.
Stergiakouli et al.: Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatric Disease and Treatment 2010; 6 551-560.
4. Thakur et al.: The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD. BMC Psychiatry 2010; 10: 50.