A three-pronged analysis confirms the association of the serotoninergic system with attention deficit hyperactivity disorder

Abstract

Background: The serotonin transporter (SERT), encoded by the solute carrier family 6 number 4 (SLC6A4) gene, controls serotonin (5-HT) availability and is essential for the regulation of behavioral traits. Two SLC6A4 genetic variants, 5-HTTLPR and STin2, were widely investigated in patients with various neurobehavioral disorders, including attention deficit hyperactivity disorder (ADHD).

Methods: We analyzed the association of the 5-HTTLPR (L/S) and STin2 (10/12) variants, plasma 5-HT, and 5-hydroxyindole acetic acid (5-HIAA), as well as SERT messenger RNA (mRNA) with ADHD in the eastern Indian subjects. Nuclear families with ADHD probands (n = 274) and ethnically matched controls (n = 367) were recruited following the Diagnostic and Statistical Manual of Mental Disorders. Behavioral traits, executive function, and intelligence quotient (IQ) of the probands were assessed using the Conner's Parent Rating Scale - Revised, Parental Account of Children's Symptoms (PACS), Barkley Deficit in Executive Functioning-Child and Adolescent Scale, and Wechsler Intelligence Scale for Children-III, respectively. After obtaining informed written consent, peripheral blood was collected to analyze genetic variants, plasma 5-HT, 5-HIAA, and SERT mRNA expression.

Results: ADHD probands showed a higher frequency of the 5-HTTLPR "L" allele and "L/L" genotype (P < 0.05), lower 5-HIAA level, and higher SERT mRNA expression. Scores for behavioral problems and hyperactivity were higher in the presence of the "S" allele and "S/S" genotype, while executive deficit was higher in the presence of the "L" allele. IQ score was lower in the presence of the STin2 "12" allele and L-12 haplotype.

Conclusion: Data obtained indicate a significant association of the serotoninergic system with ADHD, warranting further in-depth investigation.

Keywords: 5-HTT-linked polymorphic region; 5-Hydroxyindole acetic acid; 5-Serotonin; Attention deficit hyperactivity disorder; SERT mRNA.