A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity

Abstract

This study presents preliminary evidence of an association between polymorphic variation in the gene for monoamine oxidase-A (MAOA) and interindividual variability in aggressiveness, impulsivity and central nervous system (CNS) serotonergic responsivity. An apparently functional 30-bp VNTR in the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR), as well as a dinucleotide repeat in intron 2 (MAOA-CAn), was genotyped in a community sample of 110 men. All participants had completed standard interview and questionnaire measures of impulsivity, hostility and lifetime aggression history; in a majority of subjects (n=75), central serotonergic activity was also assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). The four repeat variants of the MAOA-uVNTR polymorphism were grouped for analysis (alleles ‘1+ 4’ vs. ‘2+3’) based on prior evidence of enhanced transcriptional activity in MAOA promoter constructs with alleles 2 and 3 (repeats of intermediate length). Men in the 1/4 allele group scored significantly lower on a composite measure of dispositional aggressiveness and impulsivity (P<0.015) and showed more pronounced CNS serotonergic responsivity (P<0.02) than men in the 2/3 allele group. These associations were also significant on comparison of the more prevalent one and three alleles alone (encompassing 93% of subjects). Although in linkage disequilibrium with the MAOA-uVNTR polymorphism, MAOA-CAn repeat length variation did not vary significantly with respect to behavior or fenflluramine challenge in this sample. We conclude that the MAOA-uVNTR regulatory polymorphism may contribute, in part, to individual differences in both CNS serotonergic responsivity and personality traits germane to impulse control and antagonistic behavior.

Introduction

Serotonergic activity in the central nervous system (CNS) correlates negatively with aggressiveness, impulsivity and anger-related personality traits in diverse clinical, forensic and non-patient populations (e.g. Brown et al., 1979, Brown et al., 1982, Linnoila et al., 1983, Roy et al., 1988, Coccaro et al., 1989, Coccaro et al., 1995, Coccaro et al., 1997a, Coccaro et al., 1997b, Kruesi et al., 1990, Limson et al., 1991, O’Keane et al., 1992, Virkkunen et al., 1994, Cleare and Bond, 1997, Manuck et al., 1998). This generality of association suggests the possible influence of an underlying neurobehavioral dimension of individual differences. Such a dimension has been described by temperament theorists as a continuum of behavioral constraint, inhibition, or harm avoidance (Soubrié, 1986, Depue and Spoont, 1986, Cloninger, 1987, Gray, 1987, Zuckerman, 1995). Persons who exhibit ‘low’ serotonergic activity are thus thought to have a diminished capacity to restrain impulses, this disinhibition of otherwise constrained behavior reflecting, in turn, a disregard for future consequences, impaired learning, or insensitivity to cues for punishment. When conjoined with antagonistic motivation, reduced impulse control is experienced as impulsive aggression and expressed as irritability, acts of verbal aggression or physical assault, property destruction or other antisocial behavior. When self-injurious, impulsive aggression may predispose to suicide or attempted suicide, which are similarly associated with diminished serotonergic activity in clinical studies (e.g. Ågren, 1980, Rydin et al., 1982, Mann and Stanley, 1986, van Praag, 1986, Mann et al., 1992) and may be predicted from trait measures of aggressiveness and impulsivity (Mann et al., 1999).

Biologically mediated dimensions of behavioral variability have both genetic and environmental etiologies. Among twin studies of adult populations, for instance, psychometric indices of impulsivity and aggression show heritabilities of 0.30–0.70, with environmental contributions reflecting mainly ‘non-shared’ (idiosyncratic) developmental experiences (e.g. Rushton et al., 1986, Pedersen et al., 1988, Tellegen et al., 1988, Coccaro et al., 1993, Coccaro et al., 1997a, Coccaro et al., 1997b, Lyons et al., 1995, Seroczynski et al., 1999). Genetic influences on the phenotypic covariation of aggression and impulsivity measurements (that is, shared genetic effects) are also demonstrated in one recent study (Seroczynski et al., 1999). Although few investigators have directly addressed the heritability of CNS serotonergic activity (Oxenstierna et al., 1976, Meltzer and Arora, 1988, Higley et al., 1993), it is reported that first-degree relatives of personality-disordered (PD) patients who show diminished central serotonergic responsivity (indicated by a blunted prolactin response to the serotonergic agonist, fenfluramine) are more likely to have personality traits indicative of impulsive PD than the relatives of probands exhibiting larger prolactin responses (Coccaro et al., 1994b).

It is conceivable that such genetic influences stem from variation in genes coding for components of the serotonin system, including transmitter synthesis, release and reuptake, metabolism or receptor activation. We reported previously that individual differences in aggressive disposition and serotonergic function were associated with an intronic polymorphism of the gene for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis (Manuck et al., 1998). Other studies have also shown varying associations of intronic TPH polymorphisms with suicidality or hostility among diverse clinical samples (Nielsen et al., 1994, Buresi et al., 1997, Mann et al., 1997, New et al., 1998, Nielsen et al., 1998; but see also Bellivier et al., 1998, Furlong et al., 1998), although interpretation of these findings remains tentative due to dissimilarities of study population, methodology and outcome, as well as a lack of known functional variation in the TPH gene.

A second candidate gene germane to aggression/impulsivity is that coding for monoamine oxidase-A (MAOA), a degradative enzyme that preferentially catalyzes the deamination of serotonin and norepinephrine. Aggression in male transgenic mice is heightened by deletion of the MAOA gene (Cases et al., 1995) and a mutation in this gene may also be associated with human aggressive behavior. In particular, mild retardation and impulsive aggression (including arson and attempted rape) have been found to cosegregate among males of a large Dutch kindred with a chain termination mutation in the eighth exon of the MAOA gene (Brunner et al., 1993a, Brunner et al., 1993b). Although this mutation is rare and therefore not plausibly predictive of behavior in the general population, these results suggest that common allelic variation at the MAOA locus (Xp11.4–Xp11.3) might be associated with interindividual variability in impulsivity and aggressive disposition.

Recently, Sabol et al. (1998) described a variable repeat (VNTR) in the 5′-flanking region of the MAOA gene and demonstrated allele-specific variation in promotor activity in an in vitro assay system. In preliminary studies, this apparently functional length polymorphism was found to be associated with panic disorder among women (Deckert et al., 1999) and with antisocial PD in male alcoholics (Samochowiec et al., 1999). A second MAOA polymorphism (Black et al., 1991), an intronic dinucleotide CA repeat that is in linkage disequilibrium with the promotor-region MAOA polymorphism, however, was not found related to self-reported aggression or diagnosis of conduct disorder among adolescents (Vanyukov et al., 1995). The purpose of the present investigation was to further examine polymorphic variation in the MAOA gene and its possible association with aggression/impulsivity indices, as seen in an adult male, non-patient sample of community volunteers. As in our prior study of trait attributes associated with a polymorphism of the TPH gene (Manuck et al., 1999), subjects were derived from a separate investigation conducted to identify behavioral correlates of cardiovascular disease risk and risk factor modification. Several common measures of impulsiveness, hostility and aggression history were available from the parent study and, in a portion of the study sample, a fenfluramine challenge had been administered to assess individual differences in CNS serotonergic responsivity.