COMT Val 158 Met moderates the link between rank and aggression in a non-human primate

Daria Raffaella Gutleb^1,2,3, Christian Roos^4,5, Angela Noll⁵, Julia Ostner^1,2,3†, Oliver Schülke^1,2,3†

1Department of Behavioral Ecology, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology, University of Goettingen, Göttingen, Germany

2Research Group Social Evolution in Primates, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

3Leibniz ScienceCampus Primate Cognition, Göttingen, Germany

4Gene Bank of Primates, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

5Primate Genetics Laboratory, German Primate Center, Leibniz Institute for Primate Research, Göttingen, Germany

†Contributed equally as senior authors

published in Genes, Brain and Behavior 2018;17:e12443

doi: 10.1111/gbb.12443

submitted 11.09.2017, revised 22.11.2017, accepted 28.11.2017

Abstract

The COMT Val¹⁵⁸Met polymorphism is one of the most widely studied genetic polymorphisms in humans implicated in aggression and the moderation of stressful life event effects. We screened a wild primate population for polymorphisms at the COMT Val¹⁵⁸Met site and phenotyped them for aggression to test whether the human polymorphism exists and is associated with variation in aggressive behavior. Subjects were all adults from four study groups (37 males, 40 females) of Assamese macaques (Macaca assamensis) in their natural habitat (Phu Khieo Wildlife Sanctuary, Thailand).

We collected focal animal behavioral data (27 males, 36 females, 5 964 focal hours) and fecal samples for non-invasive DNA analysis. We identified the human COMT Val¹⁵⁸Met polymorphism (14 Met/Met, 41 Val/Met, 22 Val/Val). Preliminary results suggest that COMT genotype and dominance rank interact to influence aggression rates. Aggression rates increased with rank in Val/Val, but decreased in Met/Met and Val/Met individuals, with no significant main effect of COMT genotype on aggression. Further support for the interaction effect comes from time series analyses revealing that when changing from lower to hig^5her rank position Val/Val individuals decreased, whereas Met/Met individuals increased their aggression rate. Contradicting the interpretation of earlier studies, we show that the widely studied Val¹⁵⁸Met polymorphism in COMT is not unique to humans and yields similar behavioral phenotypes in a non-human primate. This study represents an important step towards understanding individual variation in aggression in a wild primate population and may inform human behavioral geneticists about the evolutionary roots of inter-individual variation in aggression.

Introduction

Catechol-O-methyltransferase (COMT) is a key enzyme in the catecholamine catabolism (Männistö & Kaakkola, 1999). It inactivates neurotransmitters in the brain, including the catecholamines dopamine, adrenaline and noradrenaline (Axelrod &

Tomchick, 1958). The COMT enzyme is encoded by the COMT gene, which is 27.22 kb in length and located on chromosome 22q11.2 in humans (Grossman et al., 1992). Since its characterization in 1958 (Axelrod & Tomchick, 1958), COMT has been under extensive investigation and has become one of the most studied candidate genes (Dickinson & Elvevåg, 2009), especially in human studies on stress and aggression (Qayyum et al., 2015).

COMT is expressed throughout the brain (Hong et al., 1998) and occupies a significant regulatory role particularly in the prefrontal cortex (PFC). COMT is not the only protein linked to dopamine clearance, as dopamine transporters remove dopamine from the synaptic cleft as well. However, due to the limited number of dopamine transporters present in the PFC, COMT accounts for more than 60 % of dopamine degradation in this brain region (Käenmäki et al., 2010; Karoum et al., 1994; Matsumoto et al., 2003; Sesack et al., 1998; Yavich et al., 2007).

Variation in catecholamine levels have been associated with aggressive behavior (Coccaro et al., 1991; Puciłowski et al., 1986; Ratey & Gordon, 1992). Dopamine levels increase shortly before, during and after aggressive interactions in rats (Tidey & Miczek, 1996) and COMT-knockout mice exhibit increased levels of aggressive behavior (Gogos et al., 1998). Catecholamine agonists elevate aggressive behavior (Volavka, 2002) and specific dopaminergic antagonists are the most frequently applied pharmacotherapy in human aggression prevention (de Almeida et al., 2005; Gualtieri & Schroeder, 1990;

McDougle et al., 1998; Yudofsky et al., 1984). COMT has been established as a promising candidate gene for the regulation of neural processes leading to aggressive behavior (Qayyum et al., 2015; Volavka et al., 2004; but see Vassos et al., 2014).

Within the COMT gene, one functional polymorphism has been repeatedly associated with aggressive phenotypes in particular – the COMT Val¹⁵⁸Met

single nucleotide polymorphism (SNP), located in exon 4 of the COMT gene. Due to a G to A transition, the amino acid valine (Val) is substituted by methionine (Met) at codon 158. This SNP influences the enzyme’s catabolizing function of synaptic dopamine (Tunbridge, 2010; Witte & Flöel, 2012). In contrast to the low-activity, thermolabile Met variant, the Val variant is considered to be the gene variant with higher enzymatic activity and heat-stability (Lotta et al., 1995). Carriers of the Met allele suffer from a ~40 % reduced enzyme activity at physiological body temperature of 37 °C (Chen et al., 2004).

In turn, the Val genotype is associated with higher dopamine degradation and presumably lower dopamine levels in the PFC.

The effects of the COMT Val¹⁵⁸Met SNP have been studied extensively in conjunction with environmental variables. For example the influence of Val¹⁵⁸Met on the severity of aggression in children (Hygen et al., 2015), antisocial behavior in attention-deficit hyperactivity disorder (ADHD, Thapar et al., 2005), impulsive aggression in females (Wagner et al., 2010), adolescent aggressive behavioral problems (Brennan et al., 2011), behavioral and emotional problems in children (Thompson et al., 2012), depressive episodes (Hosang et al., 2017), and increased reactivity to stress as part of vulnerability for psychosis (Stefanis et al., 2007; van Winkel et al., 2008) is moderated by environmental risk factors such as prenatal stress, severe and stressful life events as well as by environmental protective factors such as parental warmth.

It should be noted that studies on the influence of the COMT Val¹⁵⁸Met polymorphism on human aggression have mostly used various indirect measures of aggression. Common methods are aggression score questionnaires, such as the Overt Aggression Scale (OAS, Yudofsky et al., 1986, e.g. Han et al., 2004), the Risk Assessment for Dangerousness (RAD, e.g. Strous et al., 1997), or the Buss-Durkee Hostility Inventory (BDHI, Buss & Durkee, 1957, e.g. Wagner et al., 2010). Difficulties with comparing and interpreting these results as well as in defining and measuring aggression have been pointed out (Qayyum et al., 2015). Issues in human studies arise from not differentiating between antisocial and aggressive behavior, questionnaire heterogeneity and the use of self-reported ratings instead of data on the actual expression of aggressive behavior (Qayyum et al., 2015).

In behavioral studies on non-human primates, aggression can be quantified reliably via direct observation of aggressive interactions. The calculation of aggression

rates enables a direct quantitative comparison between individuals and species.

Aggression is an integral part of primate social behavior (de Waal, 1992). Dyadic and polyadic aggression serves to attain and maintain high social status (Chapais, 1995;

Schülke et al., 2010) and social status in turn affects health (Habig & Archie, 2015;

Sapolsky, 2005; Snyder-Mackler et al., 2016b) and Darwinian fitness (Majolo et al., 2012). As a consequence, aggression is typically directed down the dominance hierarchy (Ostner et al., 2008a; Rowell, 1971; Schino et al., 2005; Silk, 1982) and dominance also affects patterning of affiliative behavior among group members (Schino, 2001; Seyfarth, 1977; Silk et al., 2006a, 2006b). Thus, any analysis of the drivers of individual aggressive behavior in primates needs to consider that dominance rank and aggression may be tightly linked.

While COMT Val¹⁵⁸Met has been studied extensively in humans, it is currently unknown whether this polymorphism exists in non-human primates and whether or not it is associated with similar behavioral phenotypes. In this study, we aimed at extending previous findings on the role of the COMT gene and aggression by (1) identifying existing COMT polymorphisms at the Val¹⁵⁸Met site in a non-human primate, and (2) assessing the effect of genotype on aggressive behavior using direct measures of aggression rates. As the effects of COMT Val¹⁵⁸Met have been described as moderating and aggression and dominance rank are interconnected in non-human primate societies, we assessed a possible moderating effect of the polymorphism on the relationship between dominance rank and rates of overt aggression. We studied wild Assamese macaques (Macaca assamensis) living in large multimale-multifemale groups and expressing a strictly linear steep dominance hierarchy (Bernstein & Cooper, 1999;

Macdonald et al., 2013; Ostner et al., 2008a, 2011). Aggressive social interactions are ubiquitous and aggression frequencies peak during the mating season (Ostner et al., 2008a, 2011).