MAOB Rs1799836 Research Articles

Characterization of monoamine oxidase-B (MAO-B) as a biomarker of reactive astrogliosis in Alzheimer’s disease and related dementias

Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer’s disease (AD)—Aβ plaques and neurofibrillary tangles—and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aβ plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick’s disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

The MAOA rs979605 Genetic Polymorphism Is Differentially Associated with Clinical Improvement Following Antidepressant Treatment between Male and Female Depressed Patients.

Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, MAOA and MAOB, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of MAOA and MAOB genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (n = 378) and metabolite (n = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The MAOA rs979605 and MAOB rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (p = 0.012). At M6, A allele-carrying males had a lower HDRS score (n = 24, 10.9 ± 1.61) compared to AA homozygous females (n = 14, 18.1 ± 1.87; p = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (p = 0.018). Overall, CC/C females/males had a lower ratio (n = 44, 2.18 ± 0.28) compared to TT/T females/males (n = 60, 2.79 ± 0.27; p = 0.047). The MAOA rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment.

MAO-B Polymorphism Associated with Progression in a Chinese Parkinson's Disease Cohort but Not in the PPMI Cohort.

Introduction Genetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods PD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression. Results In the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients. Conclusion MAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

Functional MAOB Gene Intron 13 Polymorphism Predicts Dyskinesia in Parkinson's Disease.

Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOBCC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089–0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039–0.520]; p=0.003) than MAOBTT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

The Role of Single Nucleotide Polymorphisms of Monoamine Oxidase B, Dopamine D2 Receptor, and DOPA Decarboxylase Receptors Among Patients Treated for Parkinson\u2019s Disease

This study aimed to investigate the association between selected variants of genes related to dopamine metabolism pathways and the risk of and progression of Parkinson’s disease (PD). This prospective cohort study was conducted in one academic teaching hospital. The study was conducted on 126 patients diagnosed with idiopathic Parkinson’s disease. Blood samples were collected to conduct a genotyping of MAOB, DRD1, DRD2, and DDC genes. Genotype and allele frequencies of MAOB (rs1799836) variants were not associated with the course of PD. Genotype and allele frequencies of DRD2 (rs2283265) variants were associated with risk of dementia (p = 0.001) and resulted in parts II and III of the UPDRS scale (p = 0.001). Genotype and allele frequencies of DRD2 (rs1076560) variants were associated with risk of dementia (p = 0.001) and resulted in parts II and III of the UPDRS scale (p = 0.001). Genotype and allele frequencies of DDC (rs921451) variants were not associated with the course of PD.

Preliminary Pharmacogenetic Study to Explore Putative Dopaminergic Mechanisms of Antidepressant Action.

Background: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. Methods: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. Results: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0–2 weeks and 0–4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2–4 weeks and 0–4 weeks. Conclusions: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable.

Detention in Juvenile Correctional Facilities Is Associated with Higher Platelet Monoamine Oxidase B Activity in Males.

Juvenile delinquency is related to several biological factors, yet very few vulnerability biomarkers have been identified. Previous data suggest that the enzyme monoamine oxidase B (MAO-B) influences several personality traits linked to the propensity to engage in delinquent behavior. Building on this evidence, we assessed whether conduct disorder (CD), juvenile delinquency adjudications, or detention in a correctional facility were associated with either platelet MAO-B activity or the MAOB rs1799836 polymorphism. The study enrolled 289 medication-free male youths, including 182 individuals detained in a correctional facility (with or without a diagnosis of CD). Of the remaining 107 participants, 26 subjects had a diagnosis of CD, and 81 were mentally healthy controls. Platelet MAO-B activity was determined by spectrophotofluorometry, while MAOB rs1799836 was genotyped using qPCR. Platelet MAO-B activity, corrected for age and smoking, was significantly higher in juvenile detainees (p < 0.001), irrespective of CD diagnosis. MAOB rs1799836 was not associated with platelet MAO-B activity or with detention in a correctional facility, CD diagnosis, or delinquent behavior. These data suggest that detention in a juvenile correctional facility increases platelet MAO-B activity in male adolescents. Future studies are needed to determine the mechanisms and functional significance of MAO-B peripheral elevation in juvenile male detainees.

Clinical and Clinical-Pharmacogenetic Models for Prediction of the Most Common Psychiatric Complications Due to Dopaminergic Treatment in Parkinson's Disease.

BackgroundThe most common psychiatric complications due to dopaminergic treatment in Parkinson’s disease are visual hallucinations and impulse control disorders. Their development depends on clinical and genetic factors.MethodsWe evaluated the simultaneous effect of 16 clinical and 34 genetic variables on the occurrence of visual hallucinations and impulse control disorders. Altogether, 214 Parkinson’s disease patients were enrolled. Their demographic, clinical, and genotype data were obtained. Clinical and clinical-pharmacogenetic models were built by The Least Absolute Shrinkage and Selection Operator penalized logistic regression. The predictive capacity was evaluated with the cross-validated area under the receiver operating characteristic curve (AUC).ResultsThe clinical-pharmacogenetic index for prediction of visual hallucinations encompassed age at diagnosis (OR = 0.99), rapid eye movement (REM) sleep behavior disorder (OR = 2.27), depression (OR = 1.0002), IL6 rs1800795 (OR = 0.99), GPX1 s1050450 (OR = 1.07), COMT rs165815 (OR = 0.69), MAOB rs1799836 (OR = 0.97), DRD3 rs6280 (OR = 1.32), and BIRC5 rs8073069 (OR = 0.94). The clinical-pharmacogenetic index for prediction of impulse control disorders encompassed age at diagnosis (OR = 0.95), depression (OR = 1.75), beta-blockers (OR = 0.99), coffee consumption (OR = 0.97), NOS1 rs2682826 (OR = 1.15), SLC6A3 rs393795 (OR = 1.27), SLC22A1 rs628031 (OR = 1.19), DRD2 rs1799732 (OR = 0.88), DRD3 rs6280 (OR = 0.88), and NRG1 rs3924999 (OR = 0.96). The cross-validated AUCs of clinical and clinical-pharmacogenetic models for visual hallucinations were 0.60 and 0.59, respectively. The AUCs of clinical and clinical-pharmacogenetic models for impulse control disorders were 0.72 and 0.71, respectively. The AUCs show that the addition of selected genetic variables to the analysis does not contribute to better prediction of visual hallucinations and impulse control disorders.ConclusionsModels could be improved by a larger cohort and by addition of other types of Parkinson’s disease biomarkers to the analysis.

Relationships of Cerebrospinal Fluid Alzheimer's Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms.

The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181, p-tau199, and p-tau231), amyloid-β42 (Aβ42), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Functional monoamine oxidase B gene intron 13 polymorphism predicts putaminal dopamine turnover in de novo Parkinson's disease.

The objective of this study was to evaluate the effects of common functional polymorphisms in genes involved in dopamine metabolism on striatal dopamine turnover in de novo Parkinson's disease (PD). This was an observer-blinded cohort study investigating effects of common functional polymorphisms in dopa decarboxylase (DDC, rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT, rs4680), and dopamine transporter/solute carrier family 6 member 3 (DAT/SLC6A3, variable number tandem repeats) genes on 18 F-fluorodopa uptake and an effective distribution volume ratio (inverse of dopamine turnover) measured by 18 F-fluorodopa PET in 28 untreated PD patients. Patients carrying the MAOBCC/(C)/CT genotype (low/intermediate enzyme activity) had a lower dopamine turnover in the putamen (higher mean effective distribution volume ratio) when compared with patients with MAOBTT/(T) genotype (high enzyme activity). Striatal PET measures were not different between variants in the remaining genes. The MAOB (rs1799836) polymorphism predicts putaminal dopamine turnover in early PD with the MAOBTT allele linked to high enzyme activity leading to higher intrinsic dopamine turnover, which has been demonstrated to constitute a risk factor for motor complications. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Genetic variants of MAOB affect serotonin level and specific behavioral attributes to increase autism spectrum disorder (ASD) susceptibility in males

Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.

Monoamine oxidase and agitation in psychiatric patients

Subjects with schizophrenia or conduct disorder display a lifelong pattern of antisocial, aggressive and violent behavior and agitation. Monoamine oxidase (MAO) is an enzyme involved in the degradation of various monoamine neurotransmitters and neuromodulators and therefore has a role in various psychiatric and neurodegenerative disorders and pathological behaviors. Platelet MAO-B activity has been associated with psychopathy- and aggression-related personality traits, while variants of the MAOA and MAOB genes have been associated with diverse clinical phenotypes, including aggressiveness, antisocial problems and violent delinquency. The aim of the study was to evaluate the association of platelet MAO-B activity, MAOB rs1799836 polymorphism and MAOA uVNTR polymorphism with severe agitation in 363 subjects with schizophrenia and conduct disorder. The results demonstrated significant association of severe agitation and smoking, but not diagnosis or age, with platelet MAO-B activity. Higher platelet MAO-B activity was found in subjects with severe agitation compared to non-agitated subjects. Platelet MAO-B activity was not associated with MAOB rs1799836 polymorphism. These results suggested the association between increased platelet MAO-B activity and severe agitation. No significant association was found between severe agitation and MAOA uVNTR or MAOB rs1799836 polymorphism, revealing that these individual polymorphisms in MAO genes are not related to severe agitation in subjects with schizophrenia and conduct disorder. As our study included 363 homogenous Caucasian male subjects, our data showing this negative genetic association will be a useful addition to future meta-analyses.

Genetic Variants of Neurotransmitter‐Related Genes and miRNAs in Egyptian Autistic Patients

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

MAOA and MAOB polymorphisms and anger-related traits in suicidal participants and controls

MAOA and, to a lesser extent, MAOB polymorphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was composed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring factors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI "anger-out" subscale) in male suicidal patients compared to controls (p < 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale ("anger out") (p = 0.002). Allele frequencies of the MAOA rs909525 were associated with suicidality (p < 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relationship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted.