A functional polymorphism in the monoamine oxidase A gene promoter
TL;DR: A new polymorphism upstream of the gene for monoamine oxidase A, which consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies, may be useful as both a functional and an anonymous genetic marker for MAOA.
Abstract: We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2–10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.
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TL;DR: Recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion are illustrated.
Abstract: Using schizophrenia as an example, Meyer-Lindenberg and Weinberger review the effectiveness of the intermediate phenotype concept for characterizing the neural systems affected by risk gene variants, with a view to elucidating mechanistic aspects of brain function implicated in psychiatric disease. Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. The intermediate phenotype concept represents a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in psychiatric disease. Using imaging genetics as an example, we illustrate recent advances, challenges and implications of linking genes to structural and functional variation in brain systems related to cognition and emotion.
1,152 citations
TL;DR: These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.
Abstract: Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.
1,083 citations
TL;DR: A comprehensive meta-analytic review of the literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies found significant associations for several candidate genes including DAT1, DRD4,DRD5, 5HTT, HTR1B, and SNAP25.
Abstract: Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.
939 citations
Cites background from "A functional polymorphism in the mo..."
...to suggest that the 5 allele also results in less eYcient transcription (Meyer-Lindenberg et al. 2006; Sabol et al. 1998)....
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...…4, and 5 copies with evidence suggesting the 2 and 3 repeat alleles are less eYciently transcribed than the longer alleles (Deckert et al. 1999), though there is some evidence to suggest that the 5 allele also results in less eYcient transcription (Meyer-Lindenberg et al. 2006; Sabol et al. 1998)....
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TL;DR: This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.
Abstract: Unchecked aggression and violence exact a significant toll on human societies. Aggression is an umbrella term for behaviours that are intended to inflict harm. These behaviours evolved as adaptations to deal with competition, but when expressed out of context, they can have destructive consequences. Uncontrolled aggression has several components, such as impaired recognition of social cues and enhanced impulsivity. Molecular approaches to the study of aggression have revealed biological signals that mediate the components of aggressive behaviour. These signals may provide targets for therapeutic intervention for individuals with extreme aggressive outbursts. This Review summarizes the complex interactions between genes, biological signals, neural circuits and the environment that influence the development and expression of aggressive behaviour.
818 citations
Cites background from "A functional polymorphism in the mo..."
...For example, a repeat length polymorphism (containing a variable number of tandem repeats) that lies upstream of exon 1 in the MAOA regulatory region contains four common alleles that have three to five repeats of a 30-base pair (bp) sequenc...
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TL;DR: Pharmacological interventions such as mood stabilizers, which dampen limbic irritability, or selective serotonin reuptake inhibitors (SSRIs), which may enhance "top-down" control, as well as psychosocial interventions to develop alternative coping skills and reinforce reflective delays may be therapeutic.
Abstract: Acts of violence account for an estimated 1.43 million deaths worldwide annually. While violence can occur in many contexts, individual acts of aggression account for the majority of instances. In some individuals, repetitive acts of aggression are grounded in an underlying neurobiological susceptibility that is just beginning to be understood. The failure of “top-down” control systems in the prefrontal cortex to modulate aggressive acts that are triggered by anger provoking stimuli appears to play an important role. An imbalance between prefrontal regulatory influences and hyper-responsivity of the amygdala and other limbic regions involved in affective evaluation are implicated. Insufficient serotonergic facilitation of “top-down” control, excessive catecholaminergic stimulation, and subcortical imbalances of glutamatergic/gabaminergic systems as well as pathology in neuropeptide systems involved in the regulation of affiliative behavior may contribute to abnormalities in this circuitry. Thus, pharmacol...
781 citations
References
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TL;DR: The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5HTT expression and 5HT uptake in lymphoblasts as discussed by the authors, which is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs.
Abstract: Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.
5,072 citations
TL;DR: The results show that considerable economy and efficiency can be brought to the mapping endeavor by resorting to appropriate strategies of detecting linkage and by constructing the human genetic map on a common reference panel of families.
Abstract: The increasing number of DNA polymorphisms characterized in humans will soon allow the construction of fine genetic maps of human chromosomes. This advance calls for a reexamination of current methodologies for linkage analysis by the family method. We have investigated the relative efficiency of two-point and three-point linkage tests for the detection of linkage and the estimation of recombination in a variety of situations. This led us to develop the computer program LINKAGE to perform multilocus linkage analysis. The investigation also enables us to propose a method of location scores for the efficient detection of linkage between a disease locus, or a new genetic marker, and a linkage group previously established from a reference panel of families. The method is illustrated by an application to simulated pedigree data in a situation akin to Duchenne muscular dystrophy. These results show that considerable economy and efficiency can be brought to the mapping endeavor by resorting to appropriate strategies of detecting linkage and by constructing the human genetic map on a common reference panel of families.
2,454 citations
"A functional polymorphism in the mo..." refers methods in this paper
...Linkage and linkage disequilibrium calculations Linkage analysis was performed by using LINKAGE 5.1 software (Lathrop et al. 1984)....
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TL;DR: Analytical results indicate that isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
Abstract: Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression.
1,481 citations
"A functional polymorphism in the mo..." refers background in this paper
...…number of tandem repeats (VNTR) in the first intron (Hinds et al. 1992), a dinucleotide repeat in the second intron (Konradi et al. 1992; Black et al. 1991), a G→T substitution at position 941, a T→A substitution at position 1077, and a T→C substitution at position –1460 (Brunner et al. 1993a, b)....
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...Second, a nonsense mutation in the MAOA gene is associated with a syndrome of mild mental retardation and impulsive aggressive behavior in affected males in a single large family studied in Holland (Brunner et al. 1993a, b)....
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TL;DR: The relationship between DADR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States was investigated and the association between long alleles ofExon III and personality traits related to Novelty Seeking was confirmed.
Abstract: Twin and adoption studies suggest that 30 to 60% of the variance in many personality traits is due to inherited factors. However, there is little knowledge of the number or identity of the responsible genes, how they differ between individuals, or how their gene products interact with the developing brain and with environmental and experiential factors to generate the complex blend of attitudes and actions that comprise human temperament1. In the accompanying paper, Ebstein et al.2 have found a population association between a long allele of polymorphic exon III repeat sequence of the D4 dopamine receptor gene (DADR) and the normal personality trait of Novelty Seeking. The possibility of a causal relationship between DADR and Novelty Seeking is further supported by studies showing that the number of exon III repeats can affect the binding of ligands to the receptor3,4; that DADR is expressed in lim-bic areas involved in cognition and emotion5,6; that dopamine mediates exploratory behaviour in experimental animals7–12; that the rewarding effects of amphetamines and cocaine are related to dopamine release13; and that Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease14. We investigated the relationship between DADR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States. The association between long alleles of exon III and personality traits related to Novelty Seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than of population stratification.
1,168 citations
"A functional polymorphism in the mo..." refers background in this paper
...The subjects were participants in three NIH protocols: “Genetic Factors and Interrelationships for Cancer Risk-Related Behaviors and Complex Traits” (n=125), “Mapping Personality Traits to Genes” (n=577; Benjamin et al. 1996; Lesch et al. 1996), and “Genetic Factors and Interrelationships for Sexual Orientation, HIV Progression, Alcoholism and Psychological Traits, and Histocompatibility Antigens” (n=746; Hamer et al. 1993; Hu et al. 1995; Pattatucci and Hamer 1995)....
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...…“Genetic Factors and Interrelationships for Cancer Risk-Related Behaviors and Complex Traits” (n=125), “Mapping Personality Traits to Genes” (n=577; Benjamin et al. 1996; Lesch et al. 1996), and “Genetic Factors and Interrelationships for Sexual Orientation, HIV Progression, Alcoholism and…...
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...The subjects were participants in three NIH protocols: “Genetic Factors and Interrelationships for Cancer Risk-Related Behaviors and Complex Traits” ( n=125), “Mapping Personality Traits to Genes” ( n=577; Benjamin et al. 1996; Lesch et al. 1996), and “Genetic Factors and Interrelationships for Sexual Orientation, HIV Progression, Alcoholism and Psychological Traits, and Histocompatibility Antigens” (n=746; Hamer et al....
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TL;DR: Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, and adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
Abstract: Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.
1,165 citations
"A functional polymorphism in the mo..." refers background in this paper
...Lastly, transgenic mice with a deletion of the MAOA gene exhibit behavioral alterations, such as trembling and difficulty in righting as pups and increased aggression in adult males (Cases et al. 1995)....
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