Monoamine oxidase B gene variants associated with attention deficit hyperactivity disorder in the Indo-Caucasoid population from West Bengal

Abstract

Background: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, excessive motor activity and impulsivity detected mostly during childhood. These traits are known to be controlled by monoamine neurotransmitters, chiefly dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA) and B (MAOB), two isoenzymes bound to the outer membrane of mitochondria, are involved in the degradation of monoamines and were explored for association with ADHD in different ethnic groups. In the present study, few exonic as well as intronic MAOB variants were analyzed in ADHD probands (N = 150) and ethnically matched controls (N = 150) recruited following the Diagnostic and Statistical Manual for Mental Disorders-4(th) edition (DSM-IV). Appropriate scales were used for measuring the behavioural attributes. Gene variants were analyzed by amplification of target sites followed by DNA sequencing and data obtained were analyzed by population based statistical methods.

Results: Out of 34 variants present in the analyzed sites, only seven functional variants, rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324 and rs3027440, were found to be polymorphic. rs2283728 'C' (P = 3.45e-006) and rs3027440 'T' (P = 0.02) alleles showed higher frequencies in ADHD probands as compared to controls. rs56220155 'A' (P = 0.04) allele and 'GA' (P = 0.04) genotype showed higher frequencies in the male and female ADHD probands respectively as compared to sex-matched controls. Analysis of pairwise linkage disequilibrium revealed striking differences between probands and controls. Haplotype analysis revealed significantly higher occurrence of different haplotypes in the ADHD probands while some haplotypes were detected in the controls only. Higher scores for conduct problems were found to be associated with rs56220155 'A' (P = 0.05) allele in the male ADHD probands. Multifactor dimensionality reduction analysis showed independent as well as interactive effects of polymorphic variants which were more robust in the male probands.

Conclusions: Since all the polymorphic variants analyzed were functional, it may be inferred that MAOB gene variants are contributing to the etiology of ADHD in the Indo-Caucasoid population from eastern India which merits further in depth analysis.

Keywords: ADHD; Conduct problems; Indo-Caucasoid population; Linkage disequilibrium; MAOB; Multifactor dimensionality reduction; rs56220155.

Fig. 1

Pairwise linkage disequilibrium between the studied variants. a controls; b ADHD probands; c male controls; d male probands; e female controls; f female probands. D’ is a measure of frequency of association of alleles at 2 loci and numbers represent the D’ value expressed as a percentile. Diamonds without numbers represent D’ values of 1.0

Fig. 2

Interaction graph generated through Multifactor Dimensionality Reduction (MDR) software. a Population based analysis for male subjects; b Population based analysis for female subjects. The graphical interaction model describe the percentage of entropy (i.e. information gain or IG) in case-control status that is explained by each factor (i.e. gene variant) or two-way interaction. Two-way interactions between factors are depicted by line accompanied by a percent of entropy explained by that interaction. Values inside large boxes on nodes indicate information gain (IG) of individual/independent main effect of each polymorphic variant, whereas values inside small boxes between nodes exemplify IG of pairwise combination/interactive effects of respective variants. Positive IG values, between the nodes, indicate the synergistic interactions; whereas negative IG values indicate the redundancy between the respective nodes/variants. Schematic coloration represents a continuum from synergy to redundancy. The red lines represent a high degree of synergy. The orange lines represent moderate synergy. The golden yellow lines accompanied by a positive percent of entropy represent minimal synergy, whereas the golden yellow lines accompanied by a negative percent of entropy represent minimal redundancy. Green line represents high redundancy