MAOA genotype,social exclusion and aggression: an experimental test of a gene–environment interaction

In 2002, Caspi and colleagues provided the first epidemiological evidence that genotype may moderate individuals' responses to environmental determinants. However, in a correlational study great care must be taken to ensure the proper estimation of the causal relationship. Here, a randomized experiment was performed to test the hypothesis that the MAOA gene promoter polymorphism (MAOA‐LPR) interacts with environmental adversity in determining aggressive behavior using laboratory analogs of real‐life conditions. A sample of 57 Caucasian male students of Catalan and Spanish origin was recruited at the University of Barcelona. Ostracism, or social exclusion, was induced as environmental adversity using the Cyberball software. Laboratory aggression was assessed with the Point Subtraction Aggression Paradigm (PSAP), which was used as an analog of antisocial behavior. We also measured aggressiveness by means of the reduced version of the Aggression Questionnaire. The MAOA‐LPR polymorphism showed a significant effect on the number of aggressive responses in the PSAP (F_1,53 = 4.63, P = 0.03, partial η² = 0.08), as well as social exclusion (F_1,53 = 8.03, P = 0.01, partial η² = 0.13). Most notably, however, we found that the MAOA‐LPR polymorphism interacts significantly with social exclusion in order to provoke aggressive behavior (F_1,53 = 4.42, P = 0.04, partial η² = 0.08), remarkably, the low‐activity allele of the MAOA‐LPR polymorphism carriers in the ostracized group show significantly higher aggression scores than the rest. Our results support the notion that gene–environment interactions can be successfully reproduced within a laboratory using analogs and an appropriate design. We provide guidelines to test gene–environment interactions hypotheses under controlled, experimental settings.     

Effects of age and MAOA genotype on the neural processing of social rejection

Adolescents are often sensitive to peer rejection, a factor that might contribute to the risk of affective disorder in this age group. Previous studies suggest a significant overlap among socioaffective brain regions involved in the response to social rejection, regions continuing to develop functionally during adolescence and regions influenced by monoamine oxidase A (MAOA) polymorphism. The current study investigated whether the neural response to social rejection is functionally immature in adolescents compared with adults, and whether these responses are modulated by MAOA genotype. Blood‐oxygen‐level‐dependent response was measured with functional magnetic resonance imaging during a rejection‐themed emotional Stroop task in 19 adolescents (aged 14–16) and 16 adults (aged 23–28) genotyped for MAOA polymorphism. Similar numbers of MAOA‐L and MAOA‐H carriers were recruited to maximize power to detect genotype effects. Main effects of rejection stimuli (relative to neutral and acceptance control stimuli) were seen in predicted socioaffective brain regions. Adolescents did not show the adult pattern of modulation by rejection stimuli in the right ventrolateral prefrontal cortex, suggesting continued functional maturation of this regulatory region during adolescence. Age and genotype interacted in the left amygdala, in which the predicted effect of genotype on responses to rejection stimuli was seen in the adults, but not in the adolescents. The data suggest continued functional development of the circuitry underlying the processing of social rejection between adolescence and adulthood, and show that the effects of MAOA genotype on neural responses may vary with age.     

Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks

The low activity variant of the monoamine oxidase A (MAOA) functional promoter polymorphism, MAOA‐LPR, in interaction with adverse environments (G × E) is associated with child and adult antisocial behaviour disorders. MAOA is expressed during foetal development so in utero G × E may influence early neurodevelopment. We tested the hypothesis that MAOA G × E during pregnancy predicts infant negative emotionality soon after birth. In an epidemiological longitudinal study starting in pregnancy, using a two stage stratified design, we ascertained MAOA‐LPR status (low vs. high activity variants) from the saliva of 209 infants (104 boys and 105 girls), and examined predictions to observed infant negative emotionality at 5 weeks post‐partum from life events during pregnancy. In analyses weighted to provide estimates for the general population, and including possible confounders for life events, there was an MAOA status by life events interaction (P = 0.017). There was also an interaction between MAOA status and neighbourhood deprivation (P = 0.028). Both interactions arose from a greater effect of increasing life events on negative emotionality in the MAOA‐LPR low activity, compared with MAOA‐LPR high activity infants. The study provides the first evidence of moderation by MAOA‐LPR of the effect of the social environment in pregnancy on negative emotionality in infancy, an early risk for the development of child and adult antisocial behaviour disorders .     

The 3111T/C polymorphism interacts with stressful life events to influence patterns of sleep in females

Genetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n = 415). Gene-environment (G × E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G × E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G × E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females.     

Evidence that the methylation state of the monoamine oxidase A (MAOA) gene predicts brain activity of MAOA 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 (MAOA)—an enzyme metabolizing neurotransmitters—revealed that MAOA 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 MAOA levels (using PET and [¹¹C]clorgyline, a radiotracer with specificity for MAOA) 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 MAOA activity. In contrast, we found a robust association of the regional and CpG site-specific methylation of the core MAOA promoter with brain MAOA 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 polymorphism moderates stability of attention problems and susceptibility to life stress during adolescence

Attention problems affect a substantial number of children and adolescents and are predictive of academic underachievement and lower global adaptive functioning. Considerable variability has been observed with regard to the individual development of attention problems over time. In particular, the period of adolescence is characterized by substantial maturation of executive functioning including attentional processing, with the influence of genetic and environmental factors on individual trajectories not yet well understood. In the present investigation, we evaluated whether the monoamine oxidase A functional promoter polymorphism, MAOA‐LPR, plays a role in determining continuity of parent‐rated attention problems during adolescence. At the same time, a potential effect of severe life events (SLEs) was taken into account. A multi‐group path analysis was used in a sample of 234 adolescents (149 males, 85 females) who took part in an epidemiological cohort study at the ages of 11 and 15 years. Attention problems during early adolescence were found to be a strong predictor of attention problems in middle adolescence. However, in carriers of the MAOA‐LPR low‐activity variant (MAOA‐L), stability was found to be significantly higher than in carriers of the high‐activity variant (MAOA‐H). Additionally, only in MAOA‐L carriers did SLEs during adolescence significantly impact on attention problems at the age of 15 years, implying a possible gene × environment interaction. To conclude, we found evidence that attention problems during adolescence in carriers of the MAOA‐L allele are particularly stable and malleable to life stressors. The present results underline the usefulness of applying a more dynamic GxE perspective.     

Genes implicated in serotonergic and dopaminergic functioning predict BMI categories

Objective: This study addressed the hypothesis that variation in genes associated with dopamine function (SLC6A3, DRD2, DRD4), serotonin function (SLC6A4, and regulation of monoamine levels (MAOA) may be predictive of BMI categories (obese and overweight + obese) in young adulthood and of changes in BMI as adolescents transition into young adulthood. Interactions with gender and race/ethnicity were also examined. Methods and Procedures: Participants were a subsample of individuals from the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative sample of adolescents followed from 1995 to 2002. The sample analyzed included a subset of 1,584 unrelated individuals with genotype data. Multiple logistic regressions were conducted to evaluate the associations between genotypes and obesity (BMI > 29.9) or overweight + obese combined (BMI ≥ 25) with normal weight (BMI = 18.5–24.9) as a referent. Linear regression models were used to examine change in BMI from adolescence to young adulthood. Results: Significant associations were found between SLC6A4 5HTTLPR and categories of BMI, and between MAOA promoter variable number tandem repeat (VNTR) among men and categories of BMI. Stratified analyses revealed that the association between these two genes and excess BMI was significant for men overall and for white and Hispanic men specifically. Linear regression models indicated a significant effect of SLC6A4 5HTTLPR on change in BMI from adolescence to young adulthood. Discussion: Our findings lend further support to the involvement of genes implicated in dopamine and serotonin regulation on energy balance.     

Investigation of the functional effect of monoamine oxidase polymorphisms in human brain

Monoamine oxidase A and monoamine oxidase B ( MAOA and MAOB) have been suggested to play a role in psychiatric disorders and/or behavioral traits. We have investigated whether different polymorphisms can account for variations in enzyme activity and/or mRNA levels in human brain. Whereas several association studies have been reported previously, this is the first study of the functional effect of MAO DNA variants in human brain. Four polymorphic changes were analyzed: a VNTR located in the MAOA promoter, a VNTR located in the first intron of the MAOA gene, and two single nucleotide polymorphisms located in exon 8 of MAOA and in intron 13 of MAOB. We studied the association of the variants and the resulting haplotypes, with expression levels and enzyme activities of both monoamine oxidases in human cortical brain autopsies. We did not find a significant association of any single MAOA polymorphism with expression levels or enzyme activity in human brain. We did, however, find an association of a particular haplotype with MAOA enzyme levels ( P=0.03). Our results suggest that a novel functional polymorphism that affects enzyme activity in human brain may exist in MAOA. For MAOB, we found a significant association ( P=0.02) between the MAOB intron 13 alleles and different levels of MAOB enzyme activity in human brain. We postulate that there may be a cis-regulatory element in linkage disequilibrium with the B-SNP13 polymorphisms that alters MAOB enzyme activity in human brain.     

Modulatory role of the brain-derived neurotrophic factor Val66Met polymorphism on the effects of serious life events on impulsive aggression in borderline personality disorder

Impulsive aggression belongs to the key features of borderline personality disorder (BPD). In the development of BPD, serious life events are known to play a major role. Acute and chronic stress has been suggested to inhibit hippocampal brain-derived neurotrophic factor (BDNF) synthesis and to mediate neural plasticity in response to adverse social experiences. Recently it has been reported that the frequency of violent suicide attempts is higher in adult suicide attempters reporting severe childhood sexual abuse and carrying the Val⁶⁶Val genotype of the BDNF Val⁶⁶Met polymorphism. In this study we analysed modulating effects of BDNF Val⁶⁶Met polymorphism on the effects of physical maltreatment, rape and childhood sexual abuse on impulsive aggression. One hundred and fifty-nine BPD patients from Germany and of Caucasian descent were included. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse accounted for 23.6% of the variance of BDHI sum score. Childhood sexual abuse decreased BDHI sum score in BDNF Val/Val carriers but not in Met carriers. In contrast to previous findings this study analysing a specific gene × environment interaction in BPD patients suggests a decreasing effect of childhood sexual abuse on impulsive aggression in BPD patients, particularly in BDNF Val/Val carriers. The interrelations between serious life events, impulsive aggression and the BDNF Val⁶⁶Met polymorphism as well as their implication for BPD are far from understood and require further investigations.     

The interaction of early life experiences with COMT val158met affects anxiety sensitivity

The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene‐by‐environment interactions of the genes coding for catechol‐O‐methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA‐uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low‐active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R² = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA‐uVNTR was restricted to the male subgroup. Carriers of the low‐active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R² = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low‐active MAOA‐uVNTR alleles .     

APOC3基因SstⅠ单核苷酸多态性与冠心病、Ⅱ型糖尿病合并高甘油三酯血症的关联性研究

对许多人群研究表明 ,位于APOA1/C3/A4 /A5基因簇上的载脂蛋白C3基因 (APOC3)SstⅠ多态性与高甘油三酯血症 (Hypertriglyceridaemia ,HTG)密切相关 ,高甘油三酯是冠心病和糖尿病的独立危险因素。为探讨中国人群APOC3基因SstⅠ单核苷酸多态性与冠状动脉粥样硬化性心脏病 (coronaryatheroscleroticheartdisease,CHD)合并高甘油三酯血症 (HTG)、Ⅱ型糖尿病 (non insulin dependentdiabetesmellitus,NIDDM)合并高甘油三酯血症 (HTG)患者的相关性 ,应用聚合酶链反应 限制性片段长度多态性 (PCR RFLP)的方法 ,分析了 2 6 7例CHD患者、2 4 6例NIDDM患者及 4 91例健康对照APOC3基因SstⅠ位点 (S1/S2 )多态性。CHD组、NIDDM组和对照组的APOC3基因SstⅠ多态位点S2等位基因频率分别为 0 30 1、0 30 7和 0 2 86 ,其基因型频率和等位基因频率分布与对照组比较均无显著性差异 (P >0 0 5 )。以TG >1 90mmol/L为标准将CHD组、NIDDM组分为正常甘油三酯组 (NTG)和高甘油三酯组(HTG)发现 ,在CHD患者 ,HTG亚组S1S2基因型频率显著高于NTG亚组 (0 5 4 2 >0 35 7,χ2 =8 77,P =0 0 12 4 ) ;在NIDDM患者 ,HTG亚组S2S2基因型频率显著高于NTG亚组 (0 2 0 0 >0 0 5 5 ,χ2 =2 0 2 1,P =0 0 0 0 0 ) ,两亚组间等位基因频     

Prevalence of the Angiotensin I Converting Enzyme Gene Insertion/Deletion Polymorphism in a Healthy Turkish Population

Angiotensin converting enzyme (ACE) plays an essential role in the renin–angiotensin system. It converts angiotensin I to angiotensin II and inactivates bradykinin and tachykinins. Numerous studies have been published investigating associations of the ACE gene I/D polymorphism with various pathophysiological conditions. We examined the prevalence of the ACE I/D polymorphism in a sample of healthy volunteers from western Turkey, including 1063 healthy Turkish controls. Analysis of the ACE I/D gene polymorphisms by polymerase chain reaction found frequencies of 16.1% for the II genotype, 47.7% for the ID genotype, and 36.2% for the DD genotype. The allele frequency was 39.9% for the I alleles and 60.1% for the D allele. This study demonstrates that the allele and genotype frequency values for the Turkish population are similar to previously published frequencies for Caucasian populations.     

The 3111T/C Polymorphism Interacts With Stressful Life Events to Influence Patterns of Sleep in Females

Genetic variations in clock-relevant genes have been investigated in relation to sleep abnormalities, both in healthy populations and in mood-disorder patients with inconsistent results. Environmental influences may moderate associations between genes and phenotype. The authors examined the CLOCK 3111T/C polymorphism and several variants within the PER3 gene and their possible interaction with stressful life events in a group of female volunteers (n?=?415). Gene-environment (G?×?E) interactions and gene main effects were investigated on depressive symptoms using the Beck Depression Inventory and on change of sleep patterns (Item 16). Results showed a G?×?E interaction on alteration of sleeping pattern: the 3111C homozygous genotype reported greater disruption in sleep pattern after the experience of stressful life events. Within the PER3 gene, one G?×?E interaction was observed with rs228642 on sleep change. These findings show that the 3111T/C polymorphism is not associated with depressive symptoms, but only with symptoms of sleep change in the case of prior stressful life experiences. The combination of a sensitive genotype (3111C/C) and environmental stress increases vulnerability to circadian rhythm disruption in females. (Author correspondence: laura.mandelli@unibo.it)     

Salivary testosterone and aggression, delinquency, and social dominance in a population-based longitudinal study of adolescent males

Testosterone (T) has been found to have a stimulating effect on aggressive behavior in a wide range of vertebrate species. There is also some evidence of a positive relationship in humans, albeit less consistently. In the present study we investigated the relationship between T and aggression, dominance and delinquency over time, covering a period from early adolescence to adulthood. From a large population-based sample (n = 1.161) a subgroup of 96 boys was selected whose behavior had been assessed repeatedly by different informants from age 12 to 21 years, and who had provided multiple T samples over these years of assessment. On the whole, a decrease in aggressive and delinquent behavior was observed in a period in which T rises dramatically. Boys who developed a criminal record, had higher T levels at age 16. In addition, positive associations were observed between T and proactive and reactive aggression and self-reported delinquent behavior. Over the pubertal years different forms of aggressive and delinquent behavior were positively related to T, which may indicate that specific positive links are dependent on the social setting in which this relationship is assessed.     

Alleles distribution of polymorphic promoter region C-590T in interleukin-4 genes and Q-576r and Ile-50Val regions in IL-4 receptor gene IL-4RA in patients with HCV-infection

81 patients with confirmed HCV-infection and 48 healthy volunteers were examined. In healthy Caucasian participants living in Siberian region significant predominance of C/T genotype in promoter region C-590T of interleukin-4 (IL-4) gene and Q/Q and Ile/Val genotypes in points -50 and -576 of IL-4RA gene that codes alpha-chains of IL-4 receptor were revealed. In patients with HCV-infection predominance of C/T genotype in C-590T region in IL-4 gene (OR = 1.86), R/R genotype in Q-576R region of IL-4RA gene (OR=7.86), and Val/Val genotype in point Ile-50Val (OR = 2.6) of the same gene. Summary predictive coefficient of hepatitis C development in carriers of these genotypes approached to 95%. During analysis of role of allelic polymorphism of IL-4 genes in predisposition to hepatitis C development it is necessary to consider not only presence of allelic variants of promoter regions of the IL-4 genes, but also the polymorphism of genes coding molecules binding with this cytokine on target cells membranes and in its soluble form.     

Association of angiotensin converting enzyme gene I/D polymorphism of vitiligo in Korean population

Vitiligo (leukoderma) is an acquired idiopathic hypomelanotic disorder characterized by the circumscribed depigmented patches. Vitiligo is a polygenic disease. The exact pathogenesis is not yet known. The angiotensin converting enzyme (ACE) gene was selected as a candidate gene as ACE plays an important role in the physiology of the vasculature, blood pressure and inflammation, and its relationship with various diseases, including autoimmune diseases, has been widely investigated. The I/D polymorphism of ACE gene in vitiligo patients has not been reported. In this study, we investigated ACE gene polymorphism in 120 vitiligo patients and in 429 healthy volunteers in Korea. The ACE gene genotype distribution (P = 0.032) and allele frequency (P = 0.012) were significantly different between vitiligo patients and healthy controls. This study suggests that the ACE gene polymorphism has a strong association with the development of vitiligo in Korean patients.     

MAOA, MTHFR, and TNF-β genes polymorphisms and personality traits in the pathogenesis of migraine

Migraine is a multifactorial disease with various factors, such as genetic polymorphisms and personality traits, but the contribution of those factors is not clear. To clarify the pathogenesis of migraine, the contributions of genetic polymorphisms and personality traits were simultaneously investigated using multivariate analysis. Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms analysis and NEO-FFI personality test were performed. At first, the univariate analysis was performed to extract the contributing factors to pathogenesis of migraine. We then extracted the factors that independently contributed to the pathogenesis of migraine using multivariate stepwise logistic regression analysis. Using the multivariate analysis, three gene polymorphisms including monoamine oxidase A (MAOA) T941G, methylenetetrahydrofolate reductase (MTHFR) C677T, and tumor necrosis factor beta (TNF-β) G252Α, and the neuroticism and conscientiousness scores in NEO-FFI were selected as significant factors that independently contributed to the pathogenesis of migraine. Their odds ratios were 1.099 (per point of neuroticism score), 1.080 (per point of conscientiousness score), 2.272 (T and T/T or T/G vs G and G/G genotype of MAOA), 1.939 (C/T or T/T vs C/C genotype of MTHFR), and 2.748 (G/A or A/A vs G/G genotype of TNF-β), respectively. We suggested that multiple factors, such as gene polymorphisms and personality traits, contribute to the pathogenesis of migraine. The contribution of polymorphisms, such as MAOA T941G, MTHFR C677T, and TNF-β G252A, were more important than personality traits in the pathogenesis of migraine, a multifactorial disorder.     

Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction

Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.