Monoamine Oxidase A Promoter Research Articles

Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome

BackgroundAutism and the fragile X syndrome (FXS) are related to each other genetically and symptomatically. A cardinal biological feature of both disorders is abnormalities of cerebral cortical brain volumes. We have previously shown that the monoamine oxidase A (MAOA) promoter polymorphism is associated with cerebral cortical volumes in children with autism, and we now sought to determine whether the association was also present in children with FXS.MethodsParticipants included 47 2-year-old Caucasian boys with FXS, some of whom also had autism, as well as 34 2-year-old boys with idiopathic autism analyzed in a previous study. The MAOA promoter polymorphism was genotyped and tested for relationships with gray and white matter volumes of the cerebral cortical lobes and cerebro-spinal fluid volume of the lateral ventricles.ResultsMAOA genotype effects in FXS children were the same as those previously observed in idiopathic autism: the low activity MAOA promoter polymorphism allele was associated with increased gray and white matter volumes in all cerebral lobes. The effect was most pronounced in frontal lobe gray matter and all three white matter regions: frontal gray, F = 4.39, P = 0.04; frontal white, F = 5.71, P = 0.02; temporal white, F = 4.73, P = 0.04; parieto-occipital white, F = 5.00, P = 0.03. Analysis of combined FXS and idiopathic autism samples produced P values for these regions <0.01 and effect sizes of approximately 0.10.ConclusionsThe MAOA promoter polymorphism is similarly associated with brain structure volumes in both idiopathic autism and FXS. These data illuminate a number of important aspects of autism and FXS heritability: a genetic effect on a core biological trait of illness, the specificity/generalizability of the genetic effect, and the utility of examining individual genetic effects on the background of a single gene disorder such as FXS.

Sudden infant death syndrome (SIDS) and polymorphisms in Monoamine Oxidase A gene (MAOA): a revisit

Literature describes multiple possible links between genetic variations in the neuroadrenergic system and the occurrence of sudden infant death syndrome. The X-chromosomal Monoamine oxidase A (MAOA) is one of the genes with regulatory activity in the noradrenergic and serotonergic neuronal systems and a polymorphism of the promoter which affects the activity of this gene has been proclaimed to contribute significantly to the prevalence of sudden infant death syndrome (SIDS) in three studies from 2009, 2012 and 2013. However, these studies described different significant correlations regarding gender or age of children. Since several studies, suggesting associations between genetic variations and SIDS, were disproved by follow-up analysis, this study was conducted to take a closer look at the MAOA gene and its polymorphisms. The functional MAOA promoter length polymorphism was investigated in 261 SIDS cases and 93 control subjects. Moreover, the allele distribution of 12 coding and non-coding single nucleotide polymorphisms (SNPs) of the MAOA gene was examined in 285 SIDS cases and 93 controls by a minisequencing technique. In contrast to prior studies with fewer individuals, no significant correlations between the occurrence of SIDS and the frequency of allele variants of the promoter polymorphism could be demonstrated, even including the results from the abovementioned previous studies. Regarding the SNPs, three statistically significant associations were observed which had not been described before. This study clearly disproves interactions between MAOA promoter polymorphisms and SIDS, even if variations in single nucleotide polymorphisms of MAOA should be subjected to further analysis to clarify their impact on SIDS.

The 5HTT and MAO-A polymorphisms associate with depressive mood and climacteric symptoms in postmenopausal women

The aim of this study was to assess the influence of the 44-bp polymorphism in the 5HTTLPR (SLC 6A4) (serotonin-transporter-linked polymorphic region, solute carrier family 6 member 4) promoter region and the 30-bpVNTR (variable number of tandem repeats) polymorphism in the MAO-A (monoamine oxidase A) promoter region on the prevalence of depressive mood and the severity of climacteric symptoms in postmenopausal women. The study involved 630 women from northern Poland who had their last menstrual period at least one year before the study. The women did not abuse alcohol or cigarettes, had not been diagnosed as having endocrinological, cancerous or mental diseases, and had not received psychiatric treatment by the time. This survey-based study was performed using the following research instruments: the Beck Depression Inventory (BDI), to evaluate depressive symptoms, and the Blatt-Kupperman Menopausal Index, to measure the severity of climacteric symptoms. The average age of the women was 57.5 ± 6.4 years. Depressive symptoms of different severity according to the BDI were diagnosed in 29.2% of the women (minor-18.6%, moderate-7.1%, severe-3.5%) and according to the Blatt-Kupperman Menopausal Index were diagnosed in 42% of the women (minor-24.1%, moderate-9.2%, severe-8.7%). Allele 'l' was significantly more common in the women without climacteric symptoms than those with minor, moderate or severe climacteric complaints (p ≤ 0.05). There was a significant correlation between the severity of climacteric and depressive symptoms (p ≤ 0.05). The women who had severe climacteric symptoms also had more severe depressive symptoms. 1. The 5HTTLPR gene polymorphism contributes to climacteric symptoms in postmenopausal women. 2. The Blatt-Kupperman Menopausal Index is an instrument which can not only be used for the measurement of the severity of climacteric symptoms but also the early detection of perimenopausal women at the risk of developing depressive symptoms.

Monoamine Oxidase A Gene Polymorphism and the Pathogenesis of Sudden Infant Death Syndrome

To test the hypothesis that there is a significant association between functionally relevant allelic variants of the monoamine oxidase A (MAO-A) polymorphism and sudden infant death syndrome (SIDS). In a case-control study of 142 cases of SIDS and 280 sex-matched control cases, the distribution of allelic and genotype variants of a promoter polymorphism of the MAO-A gene was examined using polymerase chain reaction locus amplification and fluorescence based fragment length analysis. There was a significantly differential distribution of allelic and genotype variants between females with SIDS and controls. Moreover, there was a significant association between SIDS in females and allelic and genotype variants, each related to a higher transcriptional activity at the MAO-A locus. Our results suggest a role of MAO-A in female SIDS pathogenesis exerted by functionally relevant allelic and genotype variants of the MAO-A polymorphism. However, with the complex and inconsistent evidence available to date, the impact of the MAO-A promoter polymorphism on SIDS etiology remains unclear.

MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample

BackgroundAtherosclerosis is a complex process involving both genetic and epigenetic factors. The monoamine oxidase A (MAOA) gene regulates the metabolism of key neurotransmitters and has been associated with cardiovascular risk factors. This study investigates whether MAOA promoter methylation is associated with atherosclerosis, and whether this association is confounded by familial factors in a monozygotic (MZ) twin sample.MethodsWe studied 84 monozygotic (MZ) twin pairs drawn from the Vietnam Era Twin Registry. Carotid intima-media thickness (IMT) was measured by ultrasound. DNA methylation in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The association between DNA methylation and IMT was first examined by generalized estimating equation, followed by matched pair analyses to determine whether the association was confounded by familial factors.ResultsWhen twins were analyzed as individuals, increased methylation level was associated with decreased IMT at four of the seven studied CpG sites. However, this association substantially reduced in the matched pair analyses. Further adjustment for MAOA genotype also considerably attenuated this association.ConclusionsThe association between MAOA promoter methylation and carotid IMT is largely explained by familial factors shared by the twins. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Clarification of familial factors associated with DNA methylation and early atherosclerosis will provide important information to uncover clinical correlates of disease.

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAO A enzyme in healthy men

Human brain function is mediated by biochemical processes, many of which can be visualized and quantified by positron emission tomography (PET). PET brain imaging of monoamine oxidase A (MAO A)—an enzyme metabolizing neurotransmitters—revealed that MAO A levels vary widely between healthy men and this variability was not explained by the common MAOA genotype (VNTR genotype), suggesting that environmental factors, through epigenetic modifications, may mediate it. Here, we analyzed MAOA methylation in white blood cells (by bisulphite conversion of genomic DNA and subsequent sequencing of cloned DNA products) and measured brain MAO A levels (using PET and [11C]clorgyline, a radiotracer with specificity for MAO A) in 34 healthy non-smoking male volunteers. We found significant interindividual differences in methylation status and methylation patterns of the core MAOA promoter. The VNTR genotype did not influence the methylation status of the gene or brain MAO A activity. In contrast, we found a robust association of the regional and CpG site-specific methylation of the core MAOA promoter with brain MAO A levels. These results suggest that the methylation status of the MAOA promoter (detected in white blood cells) can reliably predict the brain endophenotype. Therefore, the status of MAOA methylation observed in healthy males merits consideration as a variable contributing to interindividual differences in behavior.

Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events

The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.

Meta‐analysis argues for a female‐specific role of MAOA‐uVNTR in panic disorder in four European populations

Panic disorder (PD) is a common mental disorder, ranking highest among the anxiety disorders in terms of disease burden. The pathogenesis of PD is multifactorial with significant heritability, however only a few convincing risk genes have been reported thus far. One of the most promising candidates is the gene encoding monoamine oxidase A (MAOA), due to its key role in monoaminergic neurotransmission, established validity of animal models, and the efficacy of MAO inhibitors in the treatment of PD. A promoter repeat polymorphism in MAOA (MAOA-uVNTR) impacts on gene expression; high-expression alleles have been reported to increase the risk for PD. To further scrutinize the role of this polymorphism, we performed a formal meta-analysis on MAOA-uVNTR and PD using original data from four published European (Estonian, German, Italian, and Polish) samples and genotypes from three hitherto unpublished German PD samples, resulting in the largest (n = 1,115 patients and n = 1,260 controls) genetic study on PD reported to date. In the unpublished samples, evidence for association of MAOA-uVNTR with PD was obtained in one of the three samples. Results of the meta-analysis revealed a significant and female-specific association when calculating an allelic model (OR = 1.23, P = 0.006). This sex-specific effect might be explained by a gene-dose effect causing higher MAOA expression in females. Taken together, our meta-analysis therefore argues that high-expression MAOA-uVNTR alleles significantly increase the risk towards PD in women. However, epigenetic mechanisms might obfuscate the genetic association, calling for ascertainment in larger samples as well as assessment of the MAOA promoter methylation status therein.

Different Impacts of Aquaporin 4 and MAOA Allele Variation Among Olanzapine, Risperidone, and Paliperidone in Schizophrenia

Apoptosis has been considered to be involved in schizophrenia. Water channels are modulated just before apoptosis. In the aquaporin family, aquaporin 4 (AQP-4) is most highly expressed in the brain and is supposed to play an important role in a neuronal environment. In this clinical study, we investigated the relationship between the AQP-4 polymorphism and drug response in schizophrenia under the control of the MAOA (monoamine oxidase A) promoter gene. We recruited 91 patients with schizophrenia, and they were randomized to receive olanzapine (n = 44), risperidone (n = 23), or paliperidone (n = 24). Genotyping of AQP-4 and MAOA polymorphisms was done in all patients. Patients with the AQP-4 non-C polymorphism needed a higher dosage of olanzapine for treatment (z = 4.163, P = 0.041), and patients with a short form of the MAOA polymorphism needed a higher dosage of risperidone for treatment (z = 5.124, P = 0.024). Patients who smoked cigarettes needed a higher dosage of olanzapine for treatment (z = 4.905, P = 0.027), but cigarette smoking did not affect the dosage of paliperidone. The AQP-4 polymorphism may have an effect in influencing the dosage of olanzapine. However, the roles of AQP-4 polymorphisms in the blood-brain barrier and different neuroprotective effects need further exploration in future studies.

The monoamine oxidase A gene promoter repeat and prostate cancer risk.

Amine catabolism by monoamine oxidase A (MAOA) contributes to oxidative stress, which plays a role in prostate cancer (PCa) development and progression. An upstream variable-number tandem repeat (uVNTR) in the MAOA promoter influences gene expression and activity, and may thereby affect PCa susceptibility. Caucasian (n = 2,572) men from two population-based case-control studies of PCa were genotyped for the MAOA-VNTR. Logistic regression was used to assess PCa risk in relation to genotype. Common alleles of the MAOA-VNTR were not associated with the relative risk of PCa, nor did the relationship differ by clinical features of the disease. The rare 5-copy variant (frequency: 0.5% in cases; 1.8% in controls), however, was associated with a reduced PCa risk (odds ratio, OR = 0.30, 95% CI 0.13-0.71). A rare polymorphism of the MAOA promoter previously shown to confer low expression was associated with a reduced risk of developing PCa. This novel finding awaits confirmation in other study populations.

Association Between a Functional Polymorphism in the MAOA Gene and Sudden Infant Death Syndrome

Abnormalities in the serotonergic as well as the noradrenergic neuronal systems are believed to contribute to sudden infant death syndrome (SIDS). The X-chromosomal monoamine oxidase A (MAOA) gene is of importance for both systems and up to now no systematic study on a functional polymorphism in this gene has been performed in a sufficiently large group. We investigated a functional MAOA promoter length polymorphism in 156 white SIDS cases and 260 gender- and age-matched control subjects by using capillary electrophoresis and fluorescence dye labeled primers. The pooled low-expressing alleles *2 and *3 were more frequent in the 99 male SIDS cases than in 161 male control subjects (44.4% vs 25.5%). However, there were no differences in female cases. The frequency of low expression alleles varied significantly with the age at death and were significantly more frequent in children who died between an age of 46 and 154 days than at an older age (54.9% vs 22.6%). Our results indicate a relationship between SIDS and the MAOA genotype in boys via influencing serotonergic and noradrenergic neurons in the brainstem. This locus is the first X-chromosomal locus associated with SIDS. Our results support the theory that abnormalities in the brainstem contribute to a subset of SIDS, at least in boys. Moreover, we argue that not only the serotonergic system but also other neuronal systems, among those the noradrenergic one, are involved.

Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia

This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E-35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males.

SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive

SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.

MAOA, abuse exposure and antisocial behaviour: 30-year longitudinal study

Recent studies have raised issues concerning the replicability of gene × environment (G × E) interactions involving the monoamine oxidase A (MAOA) gene in moderating the associations between abuse or maltreatment exposure and antisocial behaviour. This study attempted to replicate the findings in this area using a 30-year longitudinal study that has strong resemblance to the original research cohort. To test the hypothesis that the presence of the low-activity MAOA genotype was associated with an increased response to abuse exposure. Participants were 398 males from the Christchurch Health and Development Study who had complete data on: MAOA promoter region variable number tandem repeat genotype; antisocial behaviour to age 30; and exposure to childhood sexual and physical abuse. Regression models were fitted to five antisocial behaviour outcomes (self-reported property offending; self-reported violent offending; convictions for property/violent offending; conduct problems; hostility) observed from age 16 to 30, using measures of childhood exposure to sexual and physical abuse. The analyses revealed consistent evidence of G × E interactions, with those having the low-activity MAOA variant and who were exposed to abuse in childhood being significantly more likely to report later offending, conduct problems and hostility. These interactions remained statistically significant after control for a range of potentially confounding factors. Findings for convictions data were somewhat weaker. The present findings add to the evidence suggesting that there is a stable G × E interaction involving MAOA, abuse exposure and antisocial behaviour across the life course.

MAOA, DBH, and SLC6A4 variants in CHARGE: a case-control study of autism spectrum disorders.

Genetic factors are established to contribute to the development of autism. We examined three loci, serotonin transporter (SLC6A4), dopamine β-hydroxylase (DBH), and the variable number of tandem repeat promoter of the monoamine oxidase A (MAOA) for association with autism in participants from the Childhood Autism Risks from Genetics and the Environment (CHARGE ) Study, the first large-scale population-based case-control investigation of both environmental and genetic contributions to autism risk. Among male children enrolled in the CHARGE study we tested associations between each of the three polymorphisms and autism (AU) (n = 119), or a combined group of autism and other autism spectrum disorders (AU+ASD, which includes an additional n = 53) as compared with typically developing controls (TD, n = 137). The case-control association analysis showed neither SLC6A4 nor DBH to be statistically significantly associated with AU or ASD. However, the male children carrying 4 tandem repeats in the promoter region of the MAOA gene showed a two-fold higher risk of AU (or AU+ASD) than those carrying allele 3, adjusted for confounders (OR = 2.02, 95% CI = 1.12, 3.65, P = 0.02 for AU vs. TD, and OR = 2.05, 95% CI = 1.19, 3.53, P = 0.01 for ASD vs. TD). In addition, children of mothers homozygous for the 4 tandem repeat allele showed at least a three-fold higher risk of AU (or AU+ASD) than those with mothers homozygous for allele 3 (OR = 3.07, 95% CI = 1.19, 7.91, P = 0.02 for AU vs. TD, and OR = 3.26, 95% CI = 1.35, 7.89, P = 0.009 for AU+ASD vs. TD). These results suggest a potential role of the functional MAOA promoter alleles in the male child, the mother, or both in ASD.

Abstract 4794: Monoamine oxidase A expression correlates with cholangiocarcinoma tumor grade and survival and is suppressed via IL-6-driven hypermethylation of the promoter

Abstract The metabolism of dopamine and serotonin is dysregulated in cholangiocarcinoma (CCA), which has subsequent growth promoting effects. Monoamine oxidase A (MAOA), the enzyme responsible for the degradation of serotonin and dopamine, is switched off in CCA although the mechanism by which this occurs is unknown. MAOA transcriptional activity can be suppressed by hypermethylation. IL-6 is known to be overproduced in CCA and can control hypermethylation events. The aims of this study were to 1) Correlate MAOA expression with pathophysiological parameters of CCA; 2) determine if IL-6 drivenhypermethylation of the MAOA promoter is involved in the suppression of expression. Methods: MAOA expression was assessed in biopsy samples from 84 patients with hilar CCA, or non-malignant controls by immunohistochemistry and realtime PCR and Kaplan-Meier survival analysis and Log Rank test performed. Hypermethylation of the MAOA promoter was assessed in four CCA cell lines previously shown to have suppressed MAOA expression, in two non-malignant cholangiocyte lines (H69 and HIBEC), and in human tumor samples using bisulfite modification followed by pyrosequencing analysis. Mz-ChA-1 and H69 cells were treated with a DNA methyltransferase inhibitor (5-aza; 10μM) for 4 days to inhibit the hypermethylation followed by qPCR assessment of MAOA expression. In parallel, Mz-ChA-1 cells were treated with a neutralizing IL-6 antibody (1μg/mL) for 4 days, or IL-6 expression was knocked down by stable transfection of IL-6 shRNA plasmids and MAOA expression was assessed by qPCR. Results: MAOA expression has a negative correlation with tumor differentiation (correlation coefficient: -2.68; P=0.014&amp;lt;0.05(2-tailed)). Furthermore there was a distinct correlation between MAOA expression and total survival (10.8 ± 0.9 months for low MAOA expression vs 27.2 ± 4.3 months for moderate or strong expression group, P&amp;lt;0.01). The MAOA promoter region was hypermethylated in CCA cells, but not H69 or HIBEC and treatment with 5-aza increased MAOA expression in Mz-ChA-1 cells, but not H69 cholangiocytes. Suppression of IL-6 expression either by neutralizing antibodies or by specific knock down of expression (to 3% of the parental cell line) reversed the hypermethylation and increased the subsequent MAOA expression. Conclusions: MAOA expression correlates with both differentiation grade and overall survival of CCA patients. Aberrant IL-6 expression seen in CCA cells may drive the suppression of MAOA expression by regulating promoter methylation and subsequent MAOA gene expression. Agents that may restore MAOA expression may have therapeutic value in the treatment of CCA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4794. doi:10.1158/1538-7445.AM2011-4794

Monoamine oxidase A regulates antisocial personality in whites with no history of physical abuse

Objective Preclinical and human family studies clearly link monoamine oxidase A (MAOA) to aggression and antisocial personality (ASP). The 30–base pair variable number tandem repeat in the MAOA promoter regulates MAOA levels, but its effects on ASP in humans are unclear. Methods We evaluated the association of the variable number tandem repeat of the MAOA promoter with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ASP disorder (ASPD) traits in a community sample of 435 participants from the Hopkins Epidemiology of Personality Disorders Study. Results We did not find an association between the activity of the MAOA allele and ASPD traits; however, among whites, when subjects with a history of childhood physical abuse were excluded, the remaining subjects with low-activity alleles had ASPD trait counts that were 41% greater than those with high-activity alleles ( P < .05). Conclusion The high-activity MAOA allele is protective against ASP among whites with no history of physical abuse, lending support to a link between MAOA expression and antisocial behavior.

Questionable association between a monoamine oxidase A promoter polymorphism and sudden infant death syndrome

Sirs, We have read with interest the article “Association of dopamine transporter and monoamine oxidase molecular polymorphisms with sudden infant death syndrome and stillbirth: new insights into the serotonin hypothesis” by Filonzi et al. in a recent edition of Neurogenetics [1]. The authors have presented a study on two polymorphisms, one of those a functional length polymorphism in the promoter region of the monoamineoxidase A (MAOA) gene, in 20 cases of sudden infant death syndrome (SIDS) and five cases of stillbirth compared to healthy controls. The main conclusion from the paper seems to be that MAOA allele 4R (with increased transcriptional activity) is significantly more common in SIDS than in controls. There are, however, severe concerns that this conclusion could be incorrect: The most problematic point of the study is that the authors obviously were not aware that MAOA is an X-chromosomal locus. They tested 25 cases, 13 of these male and 12 female, and – as can be deduced from Table 2 in this paper - are of the opinion that by doing so 50 alleles are included into the study. However, they tested only 37 alleles, as males have only one allele for this X-chromosomal locus, whereas typing fewer alleles is bound to result in weaker statistical evidence. There are also other less severe but still important problems: The case sample is extremely small and inhomogeneous. In fact, this study seems to repeat the results presented in a previous publication by the same authors [2] but for five cases of stillbirth that were added. From our point of view, it might be worth to discuss whether stillbirth and SIDS might have the same biological background, but it seems to be premature to pool these entities for a disease association study. In contrast, association studies in SIDS are normally conducted on case groups of 100 or more [3, 4]. Therefore, in order to check the results by Filonzi et al. in an independent study, we typed the MAOA locus using PCR with fluorescence-labeled primers and capillary electrophoresis in small cohorts of 22 male and 21 female SIDS cases and 20 male and 21 female controls. In contrary to the findings of Filonzi et al., we found a – however, statistically insignificant – trend towards a lower incidence of allele 4 in male, but not in female SIDS cases (Table 1). Table 1 Alleles for the X-chromosomal MAOA promoter polymorphism in 22 male and 21 female SIDS victims (above) and 20 male and 21 female controls (below) We thus conclude that a potential association of SIDS and MAOA promoter polymorphism is worth to be further studied in a larger sample but that the conclusions drawn in the study by Filonzi et al. might very well be misleading. The X-chromosomal location of this polymorphism is most intriguing, as there is a male preponderance in SIDS and linkage to an X-chromosomal locus might be an explanation for this phenomenon [5].

Association of VNTR polymorphisms in the MAOA promoter and DRD4 exon 3 with heroin dependence in male Chinese addicts

Objective. To explore the involvement of variable number tandem repeat (VNTR) polymorphisms in the monoamine oxidase A (MAOA) promoter and exon 3 of the dopamine D4 receptor (DRD4) gene in heroin addiction modulate the vulnerability of individuals to heroin addiction. Methods. Eight hundred and ninety-four male heroin addicts without other psychiatric disorders, were recruited as subjects. Another community 180 males were selected randomly as controls. Results. The geno-distribution of the DRD4 exon 3 VNTR polymorphism in controls was in Hardy–Weinberg equilibrium (HWEχ2=0.925), but the distribution in heroin addicts was not (HWEχ2=28.35). The long-repeat alleles of the DRD4 exon 3 VNTR polymorphism were found more frequently in the heroin addicts (P=0.019). However, the long-repeat alleles of the MAOA promoter VNTR polymorphism were not (P=0.828). No interaction between these two VNTR polymorphisms was found by using multiple logistic regression analysis (P=0.261). Conclusion. The long-repeat allelic variants (>4-repeats) and 2-repeat allele of the DRD4 exon 3 VNTR polymorphism might be risk alleles for individual vulnerability to heroin addiction in Chinese men, but the MAOA promoter VNTR polymorphism does not mean that the partial dominant inherited mode might involved in the genetics of heroin dependence.

MAOA gene polymorphisms and response to mirtazapine in major depression

Polymorphisms in the monoamine oxidase A (MAOA) gene may influence treatment outcomes in major depression disorder (MDD). To investigate the association of MAOA genetic polymorphisms and response to mirtazapine in patients with MDD. Fifty-eight adult patients in Taiwan who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnostic criteria for MDD were given mirtazapine for 7 weeks and evaluated on days 0, 7, 14, 21, 49 using the 24-item Hamilton Rating Scale for Depression (HRSD). Remission was defined as a final HRSD <or= 10 and a 50% reduction in baseline HRSD score. Patients provided venous blood for DNA testing. The patients' response to mirtazapine treatment was compared between those who had the long-form polymorphism in the MAOA gene promoter and the short-form polymorphism. The total HRSD scores after mirtazapine treatment were significantly lower than baseline (p < 0.001). There were 10 cases (38.5%) in short from and 6 (18.8%) in long from group touched the remission stage. Patients with the short-form group had a greater response to mirtazapine (p < 0.001) than those with the long-form polymorphism after controlling for age, sex, and apolipoprotein E genetic (APOE) polymorphism. The genetic polymorphisms in the MAOA promoter region may be associated with treatment response to mirtazapine.