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enetic Contributions to Social Impulsivity andggressiveness in Vervet Monkeys

ynn A. Fairbanks, Timothy K. Newman, Julia N. Bailey, Matthew J. Jorgensen, Sherry E. Breidenthal,oel A. Ophoff, Anthony G. Comuzzie, Lisa J. Martin, and Jeffrey Rogers

ackground: Impulsivity contributes to multiple psychiatric disorders and sociobehavioral problems, and the more seriousonsequences of impulsivity are typically manifest in social situations. This study assessed the genetic contribution to impulsivity andggressiveness in a social context using a nonhuman primate model.ethods: Subjects were 352 adolescent and adult vervet monkeys from an extended multigenerational pedigree. Behavior was

ssessed in the Intruder Challenge Test, a standardized test that measures impulsivity and aggressiveness toward a stranger. Geneticnd maternal contributions to variation in the Social Impulsivity Index and its two subscales, impulsive approach and aggression,ere estimated using variance components analyses.esults: The results found significant genetic contributions to social impulsivity (h2 � .35 � .11) and to each of the subscales, witho significant influence of maternal environment. There was a high genetic correlation between the impulsive approach andggression subscales (rho � .78 � .12).onclusions: This is the first study to demonstrate heritability of social impulsivity in adolescents and adults for any nonhumanrimate species. The high genetic correlation suggests the same genes may influence variation in both impulsive approach andggression. These results provide a promising basis for identification of susceptibility loci for impulsivity and aggressiveness.

ey Words: Impulsivity, aggressiveness, genetic, nonhuman pri-ate, personality, heritability

mpulsivity has been defined as a tendency to act “onimpulse,” without forethought or without regard for conse-quences (McCown and Simon 1993). Individuals high in

mpulsivity tend to act too quickly and have difficulty inhibitingmprudent actions (Eysenck 1993; Parker and Bagby 1997;wann et al 2002). Those low in impulsivity are more cautiousnd restrained, take more time to assess situations before acting,nd are more likely to avoid risky situations. As a trait, impulsiv-ty is a contributing feature to attention-deficit/hyperactivityisorder, conduct disorder, bipolar disorder, and personalityisorders that feature antisocial, violent, and self-destructiveehavior (Moeller et al 2001). Impulsive personality is associatedith greater risk for alcohol and substance abuse, criminality,nd suicide. Impulsive aggression leads to family violence anderious problems with interpersonal relationships. Despite theide-ranging impact of impulsivity-related traits and disorders,

ittle progress has been made in developing standardized andffective methods of prevention and treatment.

Several different methods have been used to measure impul-ivity in children and adolescents, including parent, teacher, orelf-rating scales; performance on computer tasks; and directbservation of behavior in test situations (Zaparniuk and Taylor997). In studies of adult personality, this trait has usually beeneasured with self-report questionnaires specifically designed to

ssess impulsivity (Barratt et al 1987; Eysenck 1993; Zuckerman983) or has been inferred from its relationship to factors ineneral personality inventories (Clark and Watson 1999). Aggres-

rom the Neuropsychiatric Institute (LAF, JNB, MJJ, SEB) and Department ofHuman Genetics (RAO), University of California-Los Angeles; Depart-ment of Veterans Affairs (LAF), Greater Los Angeles Healthcare System,Sepulveda, California; and Department of Genetics (TKN, AGC, LJM, JR),Southwest Foundation for Biomedical Research, San Antonio, Texas.

ddress reprint requests to Lynn A. Fairbanks, Ph.D., Neuropsychiatric Insti-tute, UCLA, 760 Westwood Plaza, Los Angeles, CA 90024.

eceived August 15, 2003; revised November 25, 2003; accepted December 6,2003.

006-3223/04/$30.00oi:10.1016/j.biopsych.2003.12.005

siveness has been measured with self-report questionnaires(Brown et al 1979; Buss and Durkee 1957) or, less frequently,through aggressive responding in laboratory test situations(Cherek et al 1997).

Recent progress in statistical and molecular genetics makesthis a promising arena for advancing knowledge of the biologicalunderpinnings of impulsivity and impulsive aggressiveness. Thefirst step in identifying molecular genetic influences on traitvariation is to establish that the trait is heritable and to estimatethe degree of genetic contribution. In human studies, this hastypically been done with twin or adoption designs or extendedfamily pedigrees. There is strong and consistent support fromtwin and adoption studies for genetic contributions to variationin impulsivity. Estimates of heritability for impulsivity in studiescomparing monozygotic and dizygotic twins typically range from20% to 60%, with similar estimates for other personality traitsrelated to impulsivity (Eaves et al 1989; Eysenck 1993; Loehlin1992; McCartney et al 1990; Plomin and Stocker 1989; Seroczyn-ski et al 1999; Tellegen et al 1988). A study of older monozygoticand dizygotic twins between 50 and 96 years of age foundheritabilities of approximately 50% for the novelty seeking scalefrom the Tridimensional Personality Questionnaire, which mea-sures a dimension from impulsive to restrained (Heiman et al2003).

As with human studies, both subjective rating systems andbehavioral measures have been used to measure personalitydimensions in nonhuman primates (Capitanio 1999; Gosling2001). Impulsivity has been measured in learning and perfor-mance tasks that require response inhibition (Jentsch et al 2000).More often, impulsivity has been inferred from behaviors thatdenote risk taking and/or uncontrolled aggressiveness. For ex-ample, animals that repeatedly enter high-risk areas, such astraps, are considered to be more impulsive than those that arecautious in potentially dangerous situations (Fairbanks et al 1999;Higley et al 1996). Impulsive aggression in free-ranging monkeyshas been measured by the tendency to engage in aggressiveinteractions that lead to contact, wounding, and early mortality(Higley et al 1996; Mehlman et al 1994).

The Intruder Challenge Test is a standardized method tomeasure impulsivity in a social situation that can be used to

BIOL PSYCHIATRY 2004;55:642–647© 2004 Society of Biological Psychiatry

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ssess large numbers of animals reliably and efficiently (Fair-anks 2001). This challenge elicits species-typical reactions ofnterest, arousal, and aggression toward a social stranger (theintruder”) for both male animals and female animals, and itmplifies individual differences in characteristic reaction tenden-ies. The Social Impulsivity Index is an internally consistent scalehat reflects individual differences in response to the intruderlong a dimension from impulsive to inhibited. The indexombines rapidity of response with risky, assertive, and aggres-ive behaviors directed toward the intruder. Animals scoring highn social impulsivity rush over to the intruder immediatelyithout taking the time to assess the situation. They place

hemselves at risk of injury by standing and sitting within arm’seach and by touching, challenging, and threatening the stranger.ubscales of the index separate impulsive approaching fromggressiveness.

The validity of this scale as a measure of impulsivity has beenupported by its relationship to age and social competence inervet monkeys (Fairbanks 2001). Social Impulsivity Indexcores peak in adolescence and decline in adulthood, and theighest ranking and most socially successful individuals in theroup tend to score in the moderate range. High scores on theocial Impulsivity Index scale have also been related to lowndicators of serotonin metabolism, a neurobiological featureommonly associated with impulsivity and impulsive aggressionn humans and nonhuman primates (Coscina 1997; Fairbanks etl 2001; Linnoila et al 1993; Manuck et al 1998). Recent resultsrom a longitudinal analysis indicate that male adolescent scoresn the Social Impulsivity Index scale before leaving the homeroup are significant predictors of eventual dominance attain-ent as an adult (Fairbanks, unpublished data).This is the first report of genetic contributions to impulsivity

nd aggressiveness in adult monkeys measured in a socialontext. Variance components modeling is used to estimateenetic and maternal contributions to variation in these traits fordolescents and adults from a large multigenerational pedigreef vervet monkeys.

ethods and Materials

ubjectsAll procedures were approved by both the University of

alifornia-Los Angeles and Veterans Affairs Animal Care and Useommittees. Subjects for this analysis were 352 vervet monkeysChlorocebus aethiops, previously known as Cercopithecus ae-hiops) at the Vervet Research Colony (VRC). The sample in-luded 180 male subjects and 172 female subjects, ranging in agerom adolescent (3 years old) to older adult (mean age � 7 years,aximum age � 23 years).The animals were housed in 18 large outdoor enclosures,

arying in size from 320 sq ft to 1400 sq ft of ground area, withrom 10 to 43 animals per group. Group composition includedultiple generations of females, their immature offspring, and 1

o 3 unrelated males for 319 of the subjects. The remaining 33ubjects were housed in all-male groups. Animals in all groupsere fed ad libitum commercial laboratory chow, supplementedy fresh fruits and vegetables.

olony PedigreeCurrent members of the Vervet Research Colony are descen-

ants of 57 wild-caught vervets (29 female vervets and 28 maleervets) captured in St. Kitts and Nevis, West Indies, andntroduced into the colony between 1975 and 1985. Twenty-four

of the 29 original matrilines are now in their third to seventhgeneration. The extended VRC pedigree includes more than 1500animals from its founding in 1975 to the present. Mothers havebeen recorded for all descendants of the original founders.Paternity was originally determined for 295 individuals, using 11polymorphic microsatellite markers (Newman et al 2002). Theoriginal paternity assessments have been verified, and additionalanimals have been included in the pedigree using a new panel ofmarkers (Ophoff et al 2002). The current pedigree includes 533animals with genetically verified mothers and identified fathers inone large interrelated family. The transfer of male animalsbetween groups to simulate the natural processes of emigrationand immigration has produced a broad distribution of related-ness within and across groups.

Seven of the subjects for the present analysis were foundingfemales introduced into the colony between 1980 and 1985; theremaining 345 subjects were born at the VRC and raised by theirmothers in stable social groups.

Intruder Challenge TestDuring the Intruder Challenge Test, 3 or 4 subjects were

locked into the large outdoor portion of their home enclosure,while all other group members were confined into the indoornight room. An unfamiliar conspecific (the intruder) in anindividual cage was placed at the edge of the home enclosure,within arm’s reach of the subject animals. Male subjects weretested with an adult male intruder, and female subjects weretested with an adult female intruder.

Behavioral responses of each subject animal, including ap-proaching, interacting with and threatening the intruder, anxiety-related behaviors, redirected aggression, and indicators of gen-eralized arousal, were coded as present or absent in each minuteof the 30-minute test session. This coding system was readilylearned by observers and interrater reliability for each codedbehavior was greater than 90% after 3 to 4 training sessions(Fairbanks 2001). The tests reported here were conducted be-tween January 1998 and June 2000.

Social Impulsivity IndexThe Social Impulsivity Index was derived from factor analysis

of behavioral responses toward the stranger. This index com-bines short latency to approach with risky, assertive, and aggres-sive behaviors directed toward the intruder (standing or sittingwithin 1 meter and touching, sniffing, displaying to, and threat-ening the intruder). In the initial sample of 128 subjects, Cron-bach � for the seven-item scale was .84 (Fairbanks 2001). SocialImpulsivity Index scores were not significantly influenced byenclosure size or by group composition (mixed sex vs. all malegroups). More information on the Intruder Challenge Test andthe Social Impulsivity Index is provided in Fairbanks (2001).

Two subscales of the Social Impulsivity Index are also con-sidered here: the approach subscale includes the number ofintervals within 1 meter, sitting in 1 meter, and touching andsniffing the intruder; the aggression subscale includes threats andagonistic displays directed toward the intruder. These two sub-scales represent different aspects of impulsivity. They each havehigh internal reliability (approach subscale, � � .88; aggressionsubscale, � � .83), while the correlation between the twosubscales is more modest (� � .47).

Statistical AnalysisGenetic and maternal environmental contributions to individ-

ual variation in behavioral traits were estimated by modeling the

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henotype covariance matrix. The matrix of similarity betweenubjects is compared with the matrix of their genetic relation-hips and their shared and unique environments. The phenotypeatrix includes all possible pairs of animals in the sample. The

ariance component formula is written such that the phenotypicovariance matrix equals the genetic component (matrix ofenetic relationships among all subject pairs times the proportionf phenotypic variance attributable to genetic variation), plus thehared environmental effects (matrix of shared environmentalariables times the proportion of variation attributable to thosehared environmental effects), plus a term for the unique envi-onment variation and error.

Shared environmental effects can be incorporated into theodel by using an equivalence relationship that partitions theedigree, as described in Lange and Boehnke (1983) and Lange1986). In this analysis, we measured the effects of sharedaternal environments (m2) by incorporating a unique environ-ental value for individuals that share the same mother. This

llows us to partition out the variation that is due to sharing theame maternal environment. It should be pointed out that thisodel does not distinguish what types of maternal effects are

nfluencing the trait (mitochondrial effects, uterine environment,othering style, matrilineal dominance rank).Bivariate analysis using variance components was also used

o estimate the genetic correlation between the approach sub-cale and the aggressive subscale of the Social Impulsivity Index.or this analysis, the phenotype matrix represents the covarianceetween the two subscales. The genetic correlation indexes theimilarity of genes that contribute to variation in the two traits. Aorrelation significantly different from zero indicates the tworaits share susceptibility genes. A correlation of one indicateshat all susceptibility genes are shared.

Genetic contributions to the phenotypic covariance are esti-ated using relatedness information from the full pedigree. The

tatistical genetic analyses were conducted using SOLAR (Se-uential Oligogenic Linkage Analysis Routines), a computerackage designed for variance component and linkage analysis

n pedigrees of arbitrary size and complexity (Almasy and

igure 1. Test-retest reliability for Social Impulsivity Index scores for 70 malepart.

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Blangero 1998). The p-values for each component were calcu-lated using log likelihood ratio tests. This method compares thetwo likelihoods of nested models, and twice the differencebetween the two log likelihoods yields a test statistic, which isasymptotically distributed as a 1/2:1/2 mixture of a �2 variablewith one degree of freedom and a point mass at zero. Bivariateanalyses were performed using a Beta test version of SOLAR(205b). Genetic correlation was tested by comparing the modelwith a model where the genetic correlation was fixed to zero (noshared genes) and one (all shared genes), using log likelihoodratio tests.

Results

Scale ReliabilityFigure 1 shows the test-retest consistency of Social Impulsivity

Index scores 1) for 70 male subjects tested 2 to 9 weeks apart and2) for 56 female subjects tested 16 months apart. In both cases,there was a high degree of consistency in scores between the twotrials. The average measure intraclass correlation coefficient forthe male subjects was .83, and for the female subjects it was .89.These results suggest that the Social Impulsivity Index is a robustand reliable measure.

Effects of Age and Sex on Social ImpulsivityMean raw scores on the Social Impulsivity Index and its

components for adolescent and adult male and female subjectsare shown in Figure 2. Individuals scoring in the upper quartileof the Social Impulsivity Index approached the intruder withinthe first minute, came within 1 meter of the intruder in 21 of the30 1-minute intervals, and aggressively challenged the intruder12 times. On average, male subjects in both age groups weremore aggressive than female subjects, and adolescent and youngadult male subjects (age 3 to 5) were more likely than older malesubjects to rush over and interact with the stranger. This wasreflected in a significant effect of sex on the aggression subscale[F (1,348) � 34.7, p � .01] and significant age by sex interactions

cts (A) tested 2 to 9 weeks apart and 56 female subjects (B) tested 16 months

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or both the approach subscale [F (1,348) � 8.6, p � .01] and theggression subscale [F (1,348) � 4.7, p � .05].

To correct for effects of age and sex in the genetics analyses,he behavioral measures were standardized by sex and by age

igure 2. Mean (� SE) Social Impulsivity Index score, approach subscale,nd aggression subscale by sex and age category.

Table 1. Additive Genetic (h2) and Maternal (m2) CoBivariate Genetic Correlation (rho) between Approa

Analyses h2 (standard deviation

Univariate AnalysesSocial impulsivity index .35 (.11) p � .00003Approach subscale .25 (.10) p � .0008Aggression subscale .61 (.12) p � .0000001

Bivariate AnalysesApproach � aggression —

group (3 to 5, 6, and older). Standardized scores were calculatedby subtracting the individual scores from the mean of the age-sexclass, dividing by the SD, multiplying by 10, and adding 50. Thisproduced scores with a mean of 50 and a SD of 10.

Genetic Contributions to Variation in Social ImpulsivityThe results of the variance components analyses are shown in

Table 1. Scores on the Social Impulsivity Index were bestestimated by the full model, which included a significant geneticcomponent (h2 � .35 � .11, p � .00003) and a nonsignificantcontribution of maternal environment.

When the two subscales of the Social Impulsivity Index wereanalyzed separately, the genetic contribution was significant foreach (aggression subscale: h2 � .61 � .12; approach subscale: h2

� .25 � .10). The maternal contribution was nonzero but notsignificant for the approach subscale and was estimated to bezero for the aggression subscale.

The genetic correlation between the approach subscale andthe aggression subscale was estimated to be .78 � .12 (Table 1).This value was significantly greater than zero (p � .0002) and lessthan 1.0 (p � .0164), suggesting that there is substantial overlapin the susceptibility genes for the two traits.

Discussion

The results of these analyses indicate that there are significantgenetic contributions to individual differences in response to astranger along dimensions of impulsivity, inhibition, and aggres-siveness. The heritability of these measures in vervet monkeyswas in the same range as heritabilities typically reported forhuman personality inventories (.30–.60). As with most of thehuman studies, there was no evidence for a shared maternalcontribution to these traits.

Numerous studies of nonhuman primate development havedemonstrated environmental influences on temperament andstress responsiveness using relatively extreme manipulations ofthe early rearing environment (Clarke and Boinski 1995; Lyons etal 2000; Suomi 1999). These methods clearly demonstrate thepotential for environmental influences on temperament in non-human primates, but they do not provide estimates of the jointaction of genetic and maternal environmental influences withinthe normal range of developmental experiences. The extendedperiod of immaturity, close mother-offspring bonds, stable indi-vidual differences in maternal style, and matrilineal “inheritance”of social status found in vervets and other Old World monkeysmake it reasonable to expect maternal influences on tempera-ment (Fairbanks 1996). Nevertheless, the results of this studysuggest that, as with human studies, the shared family environ-ment does not have much influence on the development ofindividual differences in impulsivity and aggressiveness.

Statistical genetics analyses using extended pedigrees have

utions to Variation in Impulsivity Scales andd Aggression Subscales

2 (standard deviation) rho (standard deviation)

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een used to demonstrate the heritability of a variety of demo-raphic and morphometric traits such as life span, birth weight,nd adult body mass in captive nonhuman primate populationsHa et al 2002; Jaquish et al 1997; Martin et al 2002). Preliminaryvidence has also been presented for heritability of measures ofemperament and anxiety-related behaviors in infant rhesusonkeys (Champoux et al 1999; Williamson et al 2003) and

ubjective ratings of a personality factor in chimpanzees (Weisst al 2000). The study reported here is the first to measureeritability of social behavioral traits in nonhuman primates. It ishe first study to provide estimates of genetic influences onmpulsivity and aggressiveness, and it is the first estimate ofenetic and maternal effects for adult primates that had beeneared by their mothers in unmanipulated species-typical socialroups. It suggests that, as with humans, there are significantenetic contributions and little effect of shared maternal environ-ent on variation in these traits.The two subscales of the Social Impulsivity Index measured

ifferent aspects of the subjects’ responses to the intruder. Thepproach subscale is a measure of the tendency for individuals topproach and interact with an unfamiliar and potentially threat-ning stranger. The aggressiveness subscale is a measure of theendency for individuals to react with hostility and aggression inhe same situation. The former could be interpreted as being aeasure of novelty seeking, boldness, or extroversion. The latteray be more closely related to impulsive aggressiveness as it is

xpressed in personality disorders that feature antisocial, violent,nd self-destructive behavior. While these subscales are measur-ng different behaviors, the high genetic correlation (rho � .78)etween the approach and aggression subscales suggests thatverlapping sets of genes are contributing to the variation in bothspects of impulsivity.

Even though there is strong evidence for heritability ofmpulsivity in the human literature, attempts to identify specificandidate genes and susceptibility loci for impulsivity and ag-ressiveness have produced mixed results. The candidate geneith the best evidence for an association with personality traits

elated to novelty seeking and impulsivity is the dopamine D4eceptor gene (Prolo and Licinio 2002). Nevertheless, there is stillebate about the reliability and generality of the D4 findings, andven proponents recognize that variation in this gene onlyccounts for a small proportion of the variance in impulsivity-elated traits and disorders (Paterson et al 1999). Other candidateenes in serotonin, dopamine, and norepinephrine pathwaysave been studied in relationship to impulsivity-related traitsith both positive and negative results (Veenstra-VanderWeelet al 2000), but none have been confirmed in family-basednalyses.

Whole genome scans that include continuous measures ofersonality have now been reported for three studies (Cloningert al 1998; Fullerton et al 2003; Zohar et al 2003). All three havedentified susceptibility loci for scales that measure anxiety, butone of these studies have found evidence for significant linkageo scales measuring novelty seeking and impulsivity. Thus, itppears that progress is being made in mapping genes thatontribute to vulnerability for anxiety in human populations.urther research, using a variety of different approaches, iseeded to advance our understanding of genetic contributions tompulsivity and aggressiveness. The substantial heritabilities andenetic correlation for these traits found in the present studyake the pedigree at the Vervet Research Colony a promisingodel for progress in this area.

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This research was supported by National Institute of MentalHealth Grant No. R01 MH61852 (LAF), National Center forResearch Resources Grant No. NCRR R01-08781 (JR), a ForumFoundation Grant (TKN), and by departmental funds from theNeuropsychiatric Institute and the Southwest Foundation forBiomedical Research.

We thank Karin Blau, Deborah Pollack, Jill Cullen, ShollyGunter, Adriana Huff, Denise Gomez, Daniel Diekmann, andGlenville Morton for assistance with data collection and animalcare. Denise Gomez also provided assistance with the prepara-tion of the manuscript.

TKN is currently affiliated with the Laboratories of Neuroge-netics and Clinical Studies, National Institute on Alcohol Abuseand Alcoholism, Rockville, Maryland. LJM is currently affiliatedwith the Department of Pediatrics, Center for Epidemiology andBiostatistics, Cincinnati, Ohio.

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