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.

Pilot study indicate role of preferentially transmitted monoamine oxidase gene variants in behavioral problems of male ADHD probands

“…2a , Additional file 6 ). Intra-genetic pair-wise LDs were found to be same as reported earlier [ 48 , 49 ]. In the group of parents of the female probands all the variants from MAOA gene, except 30 bp-uVNTR and rs1137070, were found to be in pair-wise LDs with each other (Fig.…”

“…In the male ADHD probands, intra-genetic pair-wise LDs for MAOA and MAOB variants were found to be same as reported earlier [ 48 , 49 ]. Inter-genetic pair-wise analysis revealed strong LD of MAOA rs6323 with MAOB rs3027440, rs6324, rs3027441, rs2283727, rs2283728, and rs56220155 in the male probands (Fig.…”

“…The target regions were amplified via polymerase chain reaction (PCR) using oligonucleotides designed in the lab using the Primer3 software [ 55 ] and the amplicons were utilized for genotyping the samples either through gel electrophoresis or using Sanger sequencing by capillary electrophoresis method [ 56 ]. For sequence analysis of the amplicons, Applied Biosystems 3130 Genetic Analyzer was used [ 48 , 49 ]. Chromatograms were also analyzed manually and for the identification of heterozygous SNPs, >25% base calling was accepted.…”

“…Chromatograms were also analyzed manually and for the identification of heterozygous SNPs, >25% base calling was accepted. Detailed analytic protocols for PCR amplification and genotyping were published earlier [ 48 , 49 ].…”

“…However, worldwide only a few MAOA and MAOB gene variants were studied and the data obtained were neither consistent nor conclusive [ 31 , 35 , 37 , 44 – 47 ]. Our population-based analysis on 58 MAO gene variants revealed association of a number of variants with ADHD [ 48 , 49 ]. Due to high heritability of ADHD traits, in the present study all these variants were explored to identify familial transmission pattern.…”