Research reportThe biological basis of anger: Associations with the gene coding for DARPP-32 (PPP1R1B) and with amygdala volume
Introduction
Anger is one of the basic emotions inherent in animals and in humans across all ethnical groups. There is agreement that individual differences in anger exist from the normal to the psychopathological range. Stimuli that provoke anger are mostly related to the irritations and frustrations caused by the restriction of freedom of action or of access to resources. Anger is often combined with aggressive behaviors which in turn are a key symptom of antisocial personality disorder (APD), a psychiatric disorder according to the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV) [2]. One prominent biological oriented personality theory, the affective neuroscience personality theory, conceptualizes personality as individual differences in the basic emotion systems of the brain [22]. Anger is one of the six traits postulated and is assessed by the affective neuroscience personality scales (ANPS) [7]. This neuroscientific personality theory integrates studies from animals and humans to describe the underlying brain circuits (the RAGE system) and the neurochemical basis of anger. In animal models anger and aggression can hardly be differentiated. Based on studies using electrical brain stimulation there is agreement that the medial hypothalamus, the amygdala and the periaqueductal gray (PAG) are central parts of the RAGE system (for an overview see [22]). Besides serotonergic also dopaminergic agents are frequently used as antiaggressive drugs indicating that the dopaminergic system is related to anger [24]. Neuroanatomically the RAGE system and the SEEK system (related to incentive motivation, exploration and reward), that is predominately under mesolimbic dopaminergic control, are assumed to be mutually inhibitory [22]. The SEEK system is related to goal directed behavior and anger is most easily aroused when the availability of desired resources diminishes. Interestingly, the SEEK and the RAGE systems have close neurophysiological and anatomical linkages [22].
Molecular genetic association studies are a valuable research tool to identify the biochemical basis of anger. Based on twin and adoption studies that have proved that about 50% of the variance in anger-related behaviors is explained by genes (e.g. [5], [6]), the search for those gene loci that influence anger has begun. It is known that norepinephrine and dopamine lower the threshold for an aggressive response to environmental stimuli. Therefore, it was hypothesized that if anger-related behavior is enhanced by catecholaminergic activity, lower activity of COMT and MAO-A (resulting in a slower inactivation of catecholamines) should indirectly enhance aggression [33]. With respect to COMT, the functional Val158Met single nucleotide polymorphism (SNP) has been associated with anger-related behavior in schizophrenic patients [13], [16], [30] and in healthy subjects [28]. Also positive findings relating the MAO-A gene to anger/aggression have been reported [12], [19].
These results support the role of the dopaminergic system for anger and aggression. So far, attempts at identifying the genetic basis of these phenotypes have mainly concentrated on genes coding for receptors and enzymes involved in the metabolism of dopamine. However, it is more and more apparent that also the signal transduction of neurotransmitters has to be investigated. Recent findings have supported this hypothesis by highlighting the importance of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signalling pathway. DARPP-32 is abundantly expressed in GABAergic medium-sized spiny neurons of the neostriatum where it also integrates dopaminergic and glutamatergic neurotransmission [21], as well as in the cerebellar cortex at the level of the Purkinje cell layer [4].
DARPP-32 is phosphorylated on Thr34 by cAMP-dependent protein kinase (PKA) upon activation of the cAMP signalling pathway, for instance, by dopamine via D1 receptors. This phosphorylated form (D34) acts as a potent inhibitor of protein phosphatase-1 (PP1). PP1 has an influence on many signalling steps, by dephosphorylating receptors such as AMPA and NMDA glutamate receptors, or GABA-A receptors, voltage-gated ion channels (Na2p, L-, and N/P-Ca2p), kinases such as calcium/calmodulin kinase II, and transcription factors (e.g., CREB), etc. [8], for a review see [32].
First association studies have tested the relevance of polymorphisms on the gene encoding DARPP-32 (PPP1R1B; located on 17q12) for the dopamine related phenotypes schizophrenia, bipolar disorders, nicotine dependence, and cognitive functioning [3], [11], [15], [17], [19], [33]. rs907094, a C → T single nucleotide polymorphism located in intron 5 of the DARPP-32 gene turned out to be directly – or as part of a haplotype block – related to these dopaminergic phenotypes.
Given the importance of the dopaminergic system for anger, we tested for an association between rs907094 and the personality trait of ANGER in a sample of healthy Caucasian subjects. In addition, we hypothesized that the amygdala, a central brain structure for the processing of emotions, is a potential link between dopaminergic action and anger as it is (a) known to be involved in the processing of anger [1], [29] and (b) basolateral amygdala projections to the medial prefrontal cortex are modulated by dopamine [10]. There is also first evidence from MRI studies that the amygdala is a core region for the processing of anger. Rüsch et al. reported a gray matter volume loss in the left amygdala in patients with borderline personality disorder (BPD) as compared to healthy controls [27]. BPD is among others characterized by symptoms of anger and aggression. We therefore in a second step examined the relationship between self-reported ANGER scores and the volume of brain structures using voxel-based morphometry (VBM). Moreover, we tested for an association between structural brain differences and variations on the DARPP-32 gene.
Section snippets
Particpipants
838 healthy participants of German origin with no present or former ICD-10 diagnosis of psychopathology (327 males: age: M = 29.89, SD = 12.12; 511 females: age: M = 26.62, SD = 10.30) residing in Bonn and Heidelberg, Germany, completed the ANPS self-report questionnaire [7], representing the biological personality theory by Panksepp. Mean age for the total group was M = 27.89 (SD = 11.15) with a range between 19 and 73 years. All participants provided buccal cells, from which the DNA could be extracted
Genetic results
The genotype frequencies of rs907094 were in Hardy–Weinberg equilibrium in both studies: (association study: TT: 512 (61%), CT: 290 (35%), CC: 37 (4%); χ2 = 0.56, d.f. = 1, n.s.; MRI study: TT: 22 (47%), CT: 22 (47%), CC: 3 (6%); χ2 = 0.67, d.f. = 1, n.s.). In order to test for a stratification bias – the participants of the MRI study were a sub-sample of the genetic association study – we calculated a χ2-test. The genotype distributions do not differ significantly (χ2 = 3.77, d.f. = 2, p = 0.154) between
Discussion
The first aim of the present study was to investigate the potential role of the DARPP-32 gene for the personality trait of ANGER. The rationale for this was based on findings demonstrating that anger was influenced by the dopaminergic system [13], [16], [28], [31]. In the past genetic association studies have mainly concentrated on genes coding for receptors or enzymes related to the dopamine metabolism, signaling pathways of the dopaminergic system have been widely neglected. Recently the
Conflict of interest
There are no conflicts of interests.
Acknowledgments
Part of this work was supported by an Emmy-Noether grant (DFG FI 848/3-1) of the German Research Foundation awarded to CF.
Thank you to Ulrike Basten and Christine Stelzel (Department of Psychology, University of Heidelberg) for the recruitment of the participants in Heidelberg, Beate Newport (University of Bonn) for assistance during the brain scans and Karin Clausen (Department of Psychology, University of Bonn) for her caring overall support.
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