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Monoamine oxidase A (MAO A) is located on the X chromosome and metabolizes biogenic amines including dopamine, norepinephrine and serotonin. A functional promoter-region polymorphism of this gene has been described that has been studied in a number of mental illnesses but not in attention deficit hyperactivity disorder (ADHD). In the current study,...
Citations
... Serotonin has been demonstrated to have effects on cognitive function (focus and flexibility) and mood [40,41], whilst dopamine levels are strongly linked to working memory and attention [42,43]. Indeed, pharmaceutical inhibition of COMT has been shown to increase levels of dopamine in the Pre-Frontal Cortex and have significant effects cognitive performance [44][45][46][47][48]. Furthermore, common genetic variants of COMT and MAO, which alter the stability and/or activity of the enzymes, have been strongly linked to elements of cognitive performance [49] as well as Attention Deficit Hyperactivity Disorder (ADHD) [50][51][52] and PD [39]. The effect of COMT alleles on executive function and working memory increases with age [53,54], which may be related to known changes to dopamine signalling with ageing [42]. ...
... In addition to cholinergic activities, caffeic acid and rosmarinic acid have also been shown to potentially modulate the metabolism of monoamine neurotransmitters through inhibition of Monoamine Oxidase A (MAO-A; rosmarinic acid IC 50 [36]). This is perhaps unsurprising given the structural similarity between caffeic acid and monoamines. ...
Background
Cognitive health is of great interest to society, with neuroinflammation and systemic inflammation age-related risk factors that are linked to declines in cognitive performance. Several botanical ingredients have been suggested to have benefits in this area including Salvia officinalis (sage), which has shown anti-inflammatory effects and exhibited promising cognitive improvements in multiple human studies. The current study demonstrates anti-inflammatory effects for S. officinalis across a broad set of in vitro models in human cells, and adds further evidence to support modulation of acetylcholine and monoamine neurostransmitter levels as mechanisms that contribute towards the benefits of the herb on cognitive health.
Methods
The effect of S. officinalis extract on release of multiple cytokines and chemokines was measured in human primary intestinal epithelial cells treated with or without LPS stimulation, and Blood Brain Barrier (BBB) cells in presence or absence of recombinant IL-17A and/or Human IL-17RA/IL-17R Antibody. Antioxidant effects were also assessed in BBB cells incubated with the extract and H2O2. The anti-inflammatory effects of S. officinalis extract were further assessed based on clinically-relevant biomarker readouts across 12 human primary cell-based disease models of the BioMAP Diversity PLUS panel.
Results
S. officinalis showed significant attenuation of the release of most cytokines/chemokines into apical media in LPS-stimulated intestinal cells, but small increases in the release of markers including IL-6, IL-8 in basolateral media; where TNF-α was the only marker to be significantly reduced. S. officinalis attenuated the release of CRP and VCAM-1 from BBB cells under IL-17A induced conditions, and also decreased H2O2 induced ROS overproduction in these cells. Phenotypic profiling with the BioMAP Diversity PLUS Panel identified additional anti-inflammatory mediators, and based on a similarity search analysis suggested potential mechanistic similarity to caffeic acid and drugs known to inhibit COMT and MAO activity to modulate monoamine metabolism. Subsequent in vitro assessment showed that S. officinalis was able to inhibit the activity of these same enzymes.
Conclusions
S. officinalis extract showed anti-inflammatory effects across multiple human cell lines, which could potentially reduce peripheral inflammation and support cognitive health. S. officinalis extract also showed the ability to inhibit enzymes related to the metabolism of monoamine neurotransmitters, suggesting possible dopaminergic and serotonergic effects acting alongside proposed cholinergic effects to mediate acute cognitive performance benefits previously demonstrated for the extract.
... Lactobacillus crispatus also increased expression of the MAOB gene (Fig. 5B), encoding proteins that can degrade biogenic amines, which can act as neurotransmitters and include serotonin, dopamine, and many more neuroactive molecules of the class. A decrease in the level of these mitochondrial enzymes has been thought to worsen neurological disorders and may also be another mechanism by which commensal bacteria mitigate the effects of these chemicals (27). ...
Urgency urinary incontinence (UUI) and overactive bladder (OAB) can both potentially be influenced by commensal and urinary tract infection-associated bacteria. The sensing of bladder filling involves interplay between various components of the nervous system, eventually resulting in contraction of the detrusor muscle during micturition. This study models host responses to various urogenital bacteria, first by using urothelial bladder cell lines and then with myofibroblast contraction assays. To measure responses, we examined Ca ²⁺ influx, gene expression, and alpha smooth muscle actin deposition assays. Organisms such as Escherichia coli and Gardnerella vaginalis were found to strongly induce Ca ²⁺ influx and contraction, whereas Lactobacillus crispatus and L. gasseri did not induce this response. Additionally, supernatants from lactobacilli impeded Ca ²⁺ influx and contraction induced by uropathogens. Upon further investigation of factors associated with purinergic signaling pathways, the Ca ²⁺ influx and contraction of cells correlated with the amount of extracellular ATP produced by E. coli . Certain lactobacilli appear to mitigate this response by utilizing extracellular ATP or producing inhibitory compounds that may act as a receptor agonist or Ca ²⁺ channel blocker. These findings suggest that members of the urinary microbiota may be influencing UUI or OAB.
IMPORTANCE The ability of uropathogenic bacteria to release excitatory compounds, such as ATP, may act as a virulence factor to stimulate signaling pathways that could have profound effects on the urothelium, perhaps extending to the vagina. This may be countered by the ability of certain commensal urinary microbiota constituents, such as lactobacilli. Further understanding of these interactions is important for the treatment and prevention of UUI and OAB. The clinical implications may require a more targeted approach to enhance the commensal bacteria and reduce ATP release by pathogens.
... An upstream variable number of tandem repeat (uVNTR) polymorphism in the MAOA promoter region, which is common in the population, also has a strong impact on transcriptional efficacy, with high enzyme expression in carriers of 3.5 or 4 repeats (MAOA-H) and low enzyme expression in carriers of 2, 3, or 5 repeats (MAOA-L; Guo, Ou, Roettger, & Shih, 2008;Sabol, Hu, & Hamer, 1998). Further evidence links MAOA-L to antisocial traits and behaviors (Mertins, Schote, Hoffeld, Griessmair, & Meyer, 2011;Williams et al., 2009), and to psychiatric disorders with impulsive features including attention deficit hyperactivity disorder (Manor et al., 2002) and alcohol dependence (Contini, Marques, Garcia, Hutz, & Bau, 2006). The neurobiological mechanisms by which MAOA-L impacts aggression are incompletely understood, with the most consistent evidence converging on cortico-limbic regions. ...
Previous studies have linked the low expression variant of a variable number of tandem repeat polymorphism in the monoamine oxidase A gene (MAOA‐L) to the risk for impulsivity and aggression, brain developmental abnormalities, altered cortico‐limbic circuit function, and an exaggerated neural serotonergic tone. However, the neurobiological effects of this variant on human brain network architecture are incompletely understood. We studied healthy individuals and used multimodal neuroimaging (sample size range: 219–284 across modalities) and network‐based statistics (NBS) to probe the specificity of MAOA‐L‐related connectomic alterations to cortical‐limbic circuits and the emotion processing domain. We assessed the spatial distribution of affected links across several neuroimaging tasks and data modalities to identify potential alterations in network architecture. Our results revealed a distributed network of node links with a significantly increased connectivity in MAOA‐L carriers compared to the carriers of the high expression (H) variant. The hyperconnectivity phenotype primarily consisted of between‐lobe (“anisocoupled”) network links and showed a pronounced involvement of frontal‐temporal connections. Hyperconnectivity was observed across functional magnetic resonance imaging (fMRI) of implicit emotion processing (pFWE = .037), resting‐state fMRI (pFWE = .022), and diffusion tensor imaging (pFWE = .044) data, while no effects were seen in fMRI data of another cognitive domain, that is, spatial working memory (pFWE = .540). These observations are in line with prior research on the MAOA‐L variant and complement these existing data by novel insights into the specificity and spatial distribution of the neurogenetic effects. Our work highlights the value of multimodal network connectomic approaches for imaging genetics.
... The MAOA-uVNTR was genotyped as described by Manor et al. [27]. The MAOA-uVNTR genotypes were divided into three groups: 3/3 (low activity allele), 3/4 and 4/4 (high activity alleles) [28]. ...
Background:
Oppositional defiant disorder (ODD) is a behavioral disorder that mainly refers to a recurrent pattern of disobedient, defiant, negativistic and hostile behaviors toward authority figures. Previous studies have showed associations of serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) with behavioral and psychiatric disorders. The purposes of this study were to investigate the potential association of 5-HTT gene promoter polymorphism (5-HTTLPR) and MAOA gene polymorphism with susceptibility to ODD in a Han Chinese school population.
Methods:
The 5-HTTLPR gene polymorphism and the MAOA gene polymorphism were genotyped in a case-control study of 257 Han Chinese children (123 ODD and 134 healthy controls).
Results:
There was significant difference in the allele distribution of 5-HTTLPR (χ2 = 7.849, P = 0.005) between the ODD and control groups. Further, there were significant differences in genotype (χ2 = 5.168, P = 0.023) and allele distributions (χ2 = 10.336, P = 0.001) of the MAOA gene polymorphism that is variable-number tandem repeat (MAOA-uVNTR) between two groups. Moreover, there were significant differences in genotype (χ2 = 4.624, P = 0.032) and allele distributions (χ2 = 9.248, P = 0.002) of MAOA-uVNTR only in the male ODD and healthy groups.
Conclusions:
Our results suggest that 5-HTTLPR and MAOA-uVNTR gene variants may contribute to susceptibility to ODD. Further, MAOA-uVNTR gene polymorphism may play a role in susceptibility to ODD only in male children.
... Variants of the DRD4 gene have been associated with performance on neuropsychological tasks in children with ADHD (Faraone et al., 2014), especially the long allele (seven or more-repeats polymorphism -DRD4-LA) (Wu, Xiao, Sun, Zou, & Zhu, 2012). The long allele has been associated with different types of performance on sustained attention and inhibitory control tasks, including: (a) a greater number of commission errors (Kieling, Roman, Doyle, Hutz, & Rohde, 2006), and higher (Johnson et al., 2008) and lower reaction time variability (Bellgrove et al., 2005;Manor et al., 2002) on a sustained attention task (continuous performance test [CPT]), which are measures of inaccurate performance that has been proposed as a characteristic of ADHD (Epstein et al., 2003); and (b) higher reaction time variability, measured by the tau component in the ex-Gaussian distributional approach to an inhibitory control task (as a measure of variability in response time) (Henríquez-Henríquez et al., 2015). A higher tau component has also been found in individuals with ADHD regardless of the cognitive domain assessed (Buzy, Medoff, & Schweitzer, 2009;Johnson et al., 2007;Klein, Wendling, Huettner, Ruder, & Peper, 2006;Uebel et al., 2010). ...
... Earlier reports on this topic are inconclusive because studies used distinct sustained attention task paradigms. As a result, some found an association of DRD4-LA with higher variability (Johnson et al., 2008), while others observed lower variability (Bellgrove et al., 2005;Manor et al., 2002), and still others failed to find any relation (Boonstra et al., 2008), or did not analyze RT variability (Barkley, Smith, Fischer, & Navia, 2006;Kieling et al., 2006;Langley et al., 2004). Because of these antecedents, our study employed a CPT to focus Nigg's (2005) description that successful detection of a rare target amid many non-targets is an index of vigilance, often referred to as "sustained attention", and that a decrease in vigilance can be indexed by greater RT variability. ...
The objective of this study was to characterize an attention deficit hyperactivity disorder (ADHD) endophenotype in non‐affected parents of adolescents with a history of ADHD, based on the relationship between performance on a sustained attention test (continuous performance task, or CPT) and polymorphisms of the DRD4 gene. In a sample of 25 non‐affected parents of adolescents with ADHD history obtained from a longitudinal study of a nonclinical population, and 25 non‐affected parents of adolescents with no ADHD history, four groups were evaluated with respect to the presence or absence of the long allele polymorphism of the DRD4 gene (i.e., over seven repeats). Comparisons of CPT performance among the four study groups included the number of commission errors, the number of omission errors, mean reaction time on correct responses (MRT), and reaction time (RT) variability (mean standard deviation of RT in each block [SDRT, as variability], and the sigma and tau components of the ex‐Gaussian approach). The group of non‐affected parents of adolescents with ADHD history and at least one long allele of the DRD4 gene showed greater RT variability (measured by SDRT), which is best explained by the greater frequency of abnormally slow responses (measured by tau). An association between the presence of the long allele of the DRD4 gene polymorphism and ADHD‐like failure in CPT performance was evident in the non‐affected parents of adolescents with ADHD in childhood. These findings suggest that certain traits of CPT performance could be considered an ADHD endophenotype.
... Lawson et al. (2003) reported no association between MAOA gene polymorphisms (rs6323 and uVNTR) and ADHD in a UK population [30]. Manor et al. (2002) showed that the 4.5 repeat allele was associated with ADHD in the Israeli population [31]. Such discrepancies in the findings in the different populations need investigations in an independent population to determine the role of the MAOA gene polymorphisms on ADHD. ...
... Lawson et al. (2003) reported no association between MAOA gene polymorphisms (rs6323 and uVNTR) and ADHD in a UK population [30]. Manor et al. (2002) showed that the 4.5 repeat allele was associated with ADHD in the Israeli population [31]. Such discrepancies in the findings in the different populations need investigations in an independent population to determine the role of the MAOA gene polymorphisms on ADHD. ...
Objective: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. The genetic cause of ADHD is still unclear, but the dopaminergic, serotonergic, and noradrenergic pathways have shown a strong association. In particular, monoamine oxidase A (MAOA) plays an important role in the catabolism of these neurotransmitters, suggesting that the MAOA gene is associated with ADHD. Therefore, we evaluated the relationship between the MAOA gene polymorphisms (uVNTR and rs6323) and ADHD. Materials and methods: We collected a total of 472 Korean children (150 ADHD cases and 322 controls) using the Korean version of the Dupaul Attention Deficit Hyperactivity Disorder Rating Scales (K-ARS). Genotyping was performed by PCR and PCR-RFLP. The Behavior Assessment System for Children Second Edition (BASC-2) was used to evaluate the problem behaviors within ADHD children. Results: We observed significant associations between the rs6323 and ADHD in girls (p < 0.05) and the TT genotype was observed as a protective factor against ADHD in the recessive model (OR 0.31, 95% CI 0.100–0.950, p = 0.022). The 3.5R-G haplotype showed a significant association in ADHD boys (p = 0.043). The analysis of subtype also revealed that the 4.5R allele of uVNTR was a risk factor for the development of ADHD in the combined symptom among girls (OR 1.87, 95% CI 1.014–3.453, p = 0.031). In the BASC-2 analysis, the MAOA uVNTR polymorphism was associated with activities of daily living in ADHD boys (p = 0.017). Conclusion: These results suggest the importance of the MAOA gene polymorphisms in the development of ADHD in Korean children. A larger sample set and functional studies are required to further elucidate of our findings.
... In this backdrop of information, both MAOA and MAOB genes, located on the X chromosome [26], were considered to contribute to the etiology of ADHD [31,32,34,[44][45][46]. 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][45][46][47]. Our population-based analysis on 58 MAO gene variants revealed association of a number of variants with ADHD [48,49]. ...
... Nevertheless, MAOA and MAOB equally degrades dopamine, another monoamine neurotransmitter which also regulates human behavior [64,65] and interplays with the [66,67], making both the enzymes crucial while studying human behavior. Several investigators have tried to find out whether MAOA and MAOB confer risk of ADHD using familybased association studies, though the data obtained were inconclusive [31,[44][45][46][47]68]. In the Israeli population, family based association studies revealed significant association of MAOA 30 bp-uVNTR with ADHD [47]. ...
... Several investigators have tried to find out whether MAOA and MAOB confer risk of ADHD using familybased association studies, though the data obtained were inconclusive [31,[44][45][46][47]68]. In the Israeli population, family based association studies revealed significant association of MAOA 30 bp-uVNTR with ADHD [47]. In the Irish ADHD probands, significantly preferential transmission of MAOA rs6323 'G' allele and a haplotype was reported, while MAOB variants failed to exhibit any association [44]. ...
Background:
Attention deficit hyperactivity disorder (ADHD) is an etiologically complex childhood onset neurobehavioral disorder characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Symptom severity varies widely and boys are diagnosed more frequently than girls. ADHD probands were reported to have abnormal transmissions of dopamine, serotonin, and/or noradrenaline. Monoamine oxidase A (MAOA) and B (MAOB), mitochondrial outer membrane bound two isoenzymes, mediate degradation of these neurotransmitters and thus regulating their circulating levels. Case-control analyses in different populations, including Indians, suggested involvement of MAOA and MAOB genes in the etiology of ADHD. Due to high heritability rate of ADHD, we tested familial transmission of MAOA and MAOB variants to ADHD probands in 190 nuclear families having ADHD probands from Indo-Caucasoid ethnicity.
Methods:
Subjects were recruited following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioral traits in probands. Genotyping was performed through PCR-based amplification of target sites followed by DNA-sequencing and/or gel-electrophoresis. Data obtained were analyzed by family based statistical methods.
Results:
Out of 58 variants present in the analyzed sites only 15 were found to be polymorphic (30 bp-uVNTR, rs5906883, rs1465107, rs1465108, rs5905809, rs5906957, rs6323, rs1137070 from MAOA and rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324, rs3027440 from MAOB). Statistically significant maternal transmission of alleles to male probands was observed for MAOA rs5905809 ‘G’ (p = 0.04), rs5906957 ‘A’ (p = 0.04), rs6323 ‘G’ (p = 0.0001) and MAOB rs56220155 ‘A’ (p = 0.002), rs2283728 ‘C’ (p = 0.0008), rs2283727 ‘C’ (p = 0.0008), rs3027441 ‘T’ (p = 0.003), rs6324 ‘C’ (p = 0.003), rs3027440 ‘T’ (p = 0.0002). Significantly preferential maternal transmissions of different haplotype combinations to male probands were also noticed (p < 0.05), while female probands did not reveal such transmission bias. Behavioral traits of male probands exhibited significant association with gene variants. Age of the mother at pregnancy also revealed association with risk variants of male probands.
Conclusions:
It may be inferred that the MAOA and MAOB variants may contribute to the etiology of ADHD in the Indo-Caucasoid population and could be responsible for higher occurrence of ADHD in the boys.
... At the same time, researchers from across several disciplines have identified the importance of including biological and genetic risk factors when discussing the development of self-control. Results from behavioral genetic research has demonstrated that genetic factors account for a moderate to large proportion of the variance in self-control Beaver et al., 2009;Boisvert, Wright, Knopik, & Vaske, 2012, 2013, while molecular genetic studies have identified specific genes related to the serotonergic and dopaminergic systems that explain variation in self-control and self-regulation (Berman, Ozkaragoz, Young, & Noble, 2002;Huang et al., 2004;Manor et al., 2001Manor et al., , 2002Manuck, Flory, Ferrell, Mann, & Muldoon, 2000;Passamonti et al., 2006;Rowe et al., 2001). ...
... Further, based on serotonergic function, low levels of serotonin metabolite in cerebrospinal fluid has been associated with disinhibition and impulsive behaviors in both animal and human models (Brown & Linnoila, 1990). Variation in genes related to serotonergic function including the monoamine oxidase A (MAOA) gene and the serotonin transporter gene (SLC6A4) has also been linked to self-regulation dysfunction (Frankle et al., 2005;Huang et al., 2004;Manor et al., 2001Manor et al., , 2002Manuck et al., 2000;Passamonti et al., 2006). ...
Purpose: The current study seeks to examine how two widely studied serotonergic polymorphisms, MAOA-uVNTR and 5-HTTLPR, interact with early and later life stressors to explain between-individual variation in low self-control in a genetically moderated stress sensitization model (G. ×. E. ×. E). Methods: Using a sample of male undergraduate students (n = 190), regression analyses were performed to examine three-way interactions of distal and proximal stress by MAOA-uVNTR and 5-HTTLPR separately, while controlling for age, race, parenting, and peer delinquency. Results: Results suggest that MAOA-uVNTR and 5-HTTLPR polymorphisms moderate individual stress sensitization in the explanation of self-control. Conclusion: Our findings highlight the need to study the etiology of self-control from both developmental and biological perspectives by demonstrating that molecular genetic variation related to serotonergic function interacts with distal stressors to increase reactivity to proximal stressors.
... DNA was isolated using standard techniques. Genotyping of the MAOA-uVNTR polymorphism was performed as described by Manor et al. [31]. According to genotype, patients and HCs were divided into two subgroups: MAOA-uVNTR high-activity allele carriers (3R/4R, 4R/4R, MAOA-H) versus homogenous MAOA-uVNTR low-activity allele carriers (2R/3R, 3R/3R, MAOA-L). ...
Background
Orbitofrontal cortex alterations have been suggested to underlie the impaired mood regulation in depression. MAOA-uVNTR (monoamine oxidase A-upstream variable number of tandem repeats) polymorphism has been reported to be associated with major depressive disorder by various studies. The influence of MAOA-uVNTR genotype on function and structure of the orbitofrontal cortex has previously been reported. In this study, we investigated the difference in orbitofrontal cortex thickness between medication-naïve female patients with major depressive disorder and healthy controls, and the influence of MAOA-uVNTR genotype on orbitofrontal cortex thickness in depression.
Methods
Thirty-one patients with major depressive disorder and 43 healthy controls were included. All participants were subjected to T1-weighted structural magnetic resonance imaging and genotyped for MAOA-uVNTR polymorphism. An automated procedure of FreeSurfer was used to analyze difference in orbitofrontal cortex thickness.
Results
Patients showed a significantly thinner left orbitofrontal cortex (F(1,71) = 7.941, p = 0.006) and right orbitofrontal cortex (F(1,71) = 17.447, p < 0.001). For the orbitofrontal cortex sub-region analysis, patients showed a significantly thinner left medial orbitofrontal cortex (F(1,71) = 8.117, p = 0.006), right medial orbitofrontal cortex (F(1,71) = 21.795, p < 0.001) and right lateral orbitofrontal cortex (F(1,71) = 9.932, p = 0.002) compared to healthy controls. No significant interaction of diagnosis and MAOA-uVNTR genotype on orbitofrontal cortex thickness was revealed.
Conclusions
Our results suggest that structural alterations of the orbitofrontal cortex may be associated with the pathophysiology of major depressive disorder. Future studies with larger sample sizes are needed to detect a possible association between MAOA-uVNTR genotype and orbitofrontal cortex thickness in depression.
... When the parents are carriers of the risk alleles, there is a similarly high rate of carrier state among their offspring, which, again, is not related to the presence or absence of ADHD. A high rate of similarity between the carrier state of the parents and their children was also observed by others, (28) but inheritance of risk alleles for ADHD is a complex process as there seems to be a preferential transmission of paternal over maternal alleles (28,29). ...
